Open Access

Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review)

  • Authors:
    • Roberto Gambari
    • Eleonora Brognara
    • Demetrios A. Spandidos
    • Enrica Fabbri
  • View Affiliations

  • Published online on: May 4, 2016     https://doi.org/10.3892/ijo.2016.3503
  • Pages: 5-32
  • Copyright: © Gambari et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects.

Introduction

MicroRNAs (miRNAs or miRs) are a family of small (19–25 nucleotides in length) non-coding RNAs that have a key role in the regulation of gene expression through the inhibition or the reduction of protein synthesis following mRNA complementary sequence base pairing (14). A single or multiple mRNAs can be targeted at the 3′ untranslated region (3′UTR), coding sequence (CDS) or 5′ untranslated region (5′UTR) sequence, and it is calculated that >60% of human mRNAs are recognized by miRNAs (14). The miRNA/mRNA interaction occurs at the level of the RNA-induced silencing complex (RISC) and causes translational repression or mRNA degradation, depending on the degree of complementarity with target mRNA sequences (58). Since their discovery and first characterization, the number of human miRNAs identified and deposited in the miRBase databases (miRBase v.21, www.mirbase.org) has increaed (it is >2,500) (916) and the research studies on miRNAs have confirmed the very high complexity of the networks constituted by miRNAs and RNA targets (1722).

Alterations in miRNA expression have been demonstrated to be associated with different human pathologies, and guided alterations of specific miRNAs have been suggested as novel approaches for the development of innovative therapeutic protocols (23,24). Studies have conclusively demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs (25,26). In general, miRNAs able to promote cancer target mRNAs coding for tumor suppressor proteins, whereas miRNAs exhibiting tumor suppressor properties usually target mRNAs coding oncoproteins (see the scheme depicted in Fig. 1A). This has a very important implication in diagnosis and/or prognosis, including the recent discovery that the pattern of circulating cell-free miRNAs in serum allows us to perform molecular analyses on these non-invasive liquid biopsies with deep diagnostic and prognostic implications. This research field has confirmed that cancer-specific miRNAs are present in extracellular body fluids, and may play a very important role in the crosstalk between cancer cells and surrounding normal cells (2732).

Interestingly, the evidence of the presence of miRNAs in serum, plasma and saliva supports their potential as an additional set of biomarkers for cancer. The extracellular miRNAs are protected by exosome-like structures, small intraluminal vesicles shed from a variety of cells (including cancer cells), with a biogenesis connected with endosomal sorting complex required for transport machinery in multivesicular bodies (29). For instance, miR-141 and miR-221/222 are predicted biomarkers in liquid biopsies from patients with colon cancer (33,34).

On the other hand, tumor-associated miRNAs are suitable targets for intervention therapeutics, as previously reported (3544) and summarized in Fig. 1B. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy) (4547), small molecule inhibitors, locked nucleic acids (LNAs) (4853), peptide nucleic acids (PNAs) (5457), morpholinos (5860), miRNA sponges (6167), mowers (68) or through miRNA masking that inhibits miRNA function by masking the miRNA binding site of a target mRNA using a modified single-stranded RNA complementary to the target sequence (6975). On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, either synthetic, or produced by plasmid or lentiviral vectors carrying miRNA sequences (7681).

2. Tumor suppressor miRNAs

Several miRNAs exhibit onco-suppressor properties by targeting mRNAs coding oncoproteins (82105). Therefore, these onco-suppressor miRNAs have been found to be often downregulated in tumors. For instance, Fernandez et al (106) recently described the intriguing tumor suppressor activity of miR-340, showing the miR-340-mediated inhibition of multiple negative regulators of p27, a protein involved in apoptosis and cell cycle progression. These interactions with oncoprotein-coding mRNA targets determine the inhibition of cell cycle progression, the induction of apoptosis and growth inhibition. The miR-340-mediated downregulation of three post-transcriptional regulators [Pumilio RNA-binding family member (PUM)1, PUM2 and S-phase kinase-associated protein 2 (SKP2)] correlates with the upregulation of p27. PUM1 and PUM2 inhibit p27 at the translational level, by rendering the p27 transcript available to interact with two oncomiRs (miR-221 and miR-222), while the oncoprotein SKP2 inhibits the CDK inhibitor at the post-translational level by triggering the proteasomal degradation of p27, showing that miR-340 affected not only the synthesis but also the decay of p27. Moreover their data confirm the recent identification of transcripts encoding several pro-invasive proteins such as c-Met, implicated in breast cancer cell migration, RhoA and Rock1, implicated in the control of the migration and invasion of osteosarcoma cells, and E-cadherin mRNA, involved in the miR-340-induced loss of intercellular adhesion (106 and refs within).

Recently, miR-18a was demonstrated to play a protective role in colorectal carcinoma (CRC) by inhibiting the proliferation, invasion and migration of CRC cells by directly targeting the TBP-like 1 (TBPL1) gene. The onco-suppressor activity of miR-18a in CRC tissues and cell lines was supported by the finding that the content of this mRNA is markedly lower in tumor cells with respect to normal control tissues and cells (107). In addition Xishan et al (108) found that miR-320a acts as a novel tumor suppressor gene in chronic myelogenous leukemia (CML) and can decrease the migratory, invasive, proliferative and apoptotic behavior of CML cells, as well as epithelial-mesenchymal transition (EMT), by attenuating the expression of the BCR/ABL oncogene. Furthermore Zhao et al (109) demonstrated that miR-449a functions as a tumor suppressor in neuroblastoma by inducing cell differentiation and cell cycle arrest. Finally, Kalinowski et al (110) and Gu et al (111) demonstrated the significant role of miR-7 in cancer which functions by directly targeting and inhibiting key oncogenic signaling molecules involved in cell cycle progression, proliferation, invasion and metastasis. A partial list of onco-suppressor miRNAs is presented in Table I.

Table I

miRNAs exhibiting tumor suppressor functions.

Table I

miRNAs exhibiting tumor suppressor functions.

MicroRNADiseaseBiological effectsTarget mRNA/pathway Authors/(Refs.)
miR-1Head and neck squamous cell carcinoma (HNSCC), prostate cancerInhibition of cell proliferation, invasion, migration and promotion of apoptosis and cell cycle arrest; affected cellular organization of F-actin and impaired tumor cell invasion and filopodia formationTAGLN2, FN1, LASP1, XPO6, TWIST1, EGFRNohata et al (112); Hudson et al (113); Chang et al (114)
miR-7Breast, ovarian cancerSuppression of cell invasion and metastasis; inhibition of the ability of breast CSCs to metastasize to the brain; inhibition of tumor metastasis and reversed EMT in EOC cell linesSETDB1, KLF4, EGFR through AKT/ERK1/2 pathwayZhang et al (115); Okuda et al (116); Zhou et al (117)
miR-let-7Breast, lung, colon, ovarian cancerInhibition of invasion and bone metastasis; reduction of tumor growth, negative regulation of cell cycle-related oncogenesRAS, MYC, HMGA2, SnailLee and Dutta (83); Sampson et al (86); Trang et al (92); Dangi-Garimella et al (118); Takamizawa et al (119); Shi et al (120); Johnson et al (121)
miR-9Gastric cancerSuppression of invasion metastasisCyclin D1, Ets1Zheng et al (122)
miR-15a; miR-16-1Chronic lymphocytic leukemia (CLL), multiple myeloma, mantle cell lymphoma, prostate cancers, gastric adenocarcinomaInduction of apoptosis; decreased tumorigenity, evading growth suppressors, resisting cell deathBcl-2, cyclin D1, WNT3AAqeilan et al (123); Calin et al (124); Pekarsky et al (125); Bonci et al (126); Kang et al (127)
miR-16GlioblastomaRepression of endothelial function and angiogenesisBmi-1Chen et al (128)
miR-18aColorectal cancerDecrease of cell migration, altered cell morphology, G1/S phase cell cycle arrest, increased apoptosisCDC42Humphreys et al (129)
miR-25Prostate cancerInhibition of extravasion in vivoαv, α6 integrinsZoni et al (130)
miR-27aAcute leukemiaInhibition of cell growth due at least in part, to increased cellular apoptosisBax and BadScheibner et al (94)
miR-29cNasopharyngeal carcinomaInhibition of invasion and metastasisCollagens, Laminin γ1Sengupta et al (131)
miR-29s (miR-29a, miR-29b1, miR-29b2, miR-29c)Lung cancer, cervical carcinogenesis, cholangiocarcinoma, hepatocellular carcinoma (HCC), mantle cell lymphoma (MCL), melanoma and acute myeloid leukemia (AML) B and T cellsDecrease in cell proliferation and an increase in cell senescence and apoptosis; decreased AML cell growth and impairement of colony formation, longer survival of treated mice; improvement of anti-leukemic activity of decitabineCDK6, Ppm1d, osteonectin, Mcl-1, KIT, SP1, Bcl-2, DNMT3A, DNMT3B, DNMTs, Tcl-1, extracellular matrix genes, FLT3, Cdc42, p85aUgalde et al (132); Garzon et al (133); Garzon et al (134); Huang et al (98); Kapinas et al (135); Mott et al (136); Fabbri et al (137); Xiong et al (138); Filkowski et al (139); Wang et al (140); Hu et al (141)
miR-30bLaryngeal carcinomaAntitumor and pro-apoptotic effect in vivo and in vitrop53 via MDM2Li and Wang (142)
miR-31Breast cancer, lung adenocarcinoma (stem cells)Inhibition of multiple steps of metastasis, including invasion, anoikis and colonizationMET-PI3K-Akt, WAVE3Hou et al (143); Valastyan et al (144); Sossey-Alaoui et al (145)
miR-33aChronic myelogenous leukemia (CML), colon carcinomaDecelerated cell proliferation; reduced tumor cell proliferationPim-1Thomas et al (95); Ibrahim et al (91)
miR-33bBreast cancer lung metastasis, osteosarcomaInhibition of stemness, migration, invasion and metastasisHMGA2, SALL4, Twist1, c-MYCLin et al (146); Xu et al (147)
miR-34aBreast, lung, colon, kidney, prostate, bladder, pancreatic, bone and lung cancer, and melanomaBlocking of tumor growth; inhibition of cell migration, invasion and metastasis of cancer cells; suppression of prostate CSCs and metastasis; decrease in the production of the chemokine CCL22; disturbance of the bone metastatic nicheBcl-2, cyclin D1, cyclin E2, CDK4, CDK6, c-MYC, MET, N-MYC, SIRT1, Fra-1, CD44, CCL44, Tgif2He et al (148); Bommer et al (149); Fujita et al (150); Leucci et al (151); Saito et al (152); Wei et al (153); Yamakuchi et al (154); Lodygin et al (155); Wiggins et al (90); Yang et al (156); Yang et al (157); Liu et al (158); Krzeszinski et al (159)
miR-34bBreast, ovarian, endometrial cancerTumor suppressor in estrogen-dependent cell growthCyclin D1 and JAG1 in ER+/wild-type p53Lee et al (102); Wang et al (160)
miR-34cBreast, ovarian cancer, lung metastasisInhibition of cell migration; invasion and lung metastasisFra-1Yang et al (156); Yu et al (161)
miR-101-3pSalivary gland adenoid cystic carcinomaSuppression of cell proliferation, invasion and enhanced chemotherapeutic sensitivityPim-1Liu et al (162)
miR-122aLiver tumor and diseaseReduced disease manifestation and tumor incidenceKlf6Tsai et al (163)
miR-124Intrahepatic, bladder, colorectal and lung cancer, osteosarcoma, neuroblastoma, gliomaModulation of the intercellular adhesion of leading cells; inhibition of EMT in vitro and suppression of intrahepatic and pulmonary metastasis in vivo; suppression of motility and angiogenesis in bladder cancer cells, of migration and invasion of U-2OS and Saos-2 cellsIntegrin β1, ROCK2, EZH2, UHRF1, ROR2, MYO10, DNMT3B, PTB/PKM1/ PKM2 cascadeTaniguchi et al (164); Huang et al (165); Kato et al (166); Zheng et al (167); Wang et al (168); Zhang et al (169); Sun et al (170); Sun et al (171); Chen et al (172); Zhang et al (173)
miR-125aCervical cancerSuppression of tumor growth, invasion, metastasisARID3B, STAT3Cowden Dahl et al (174); Fan et al (175)
miR-126Non-small cell lung cancer cells, breast, thyroid, liver, colorectal cancer, osteosarcomaTumor suppressor genes involved in the control of cell proliferation and cell death, cell migration and blood vessel formation; inhibition of cell proliferation, invasion, migration and tumorigenesis; suppression of tumor metastasis and angiogenesis in hepatocellular carcinomaEGFL7, SLC7A5, ADAM9, IGFBP2, PITPNC1, MERTK, SDF-1&aSun et al (176); Xiong et al (177); Wang et al (178); Wen et al (179); Jiang et al (180); Du et al (181); Zhang et al (182); Png et al (183)
miR-128Glioblastoma, hepatocellular carcinoma, acute lymphoblastic leukemiaInhibition of angiogenesis and proliferation, inhibition of tumor cell progressionWEE1, p70S6K1, Msi1, E2F3a, Bmi-1, EGFR, PDGFRA, PIK3R1Shi et al (184); Wuchty et al (185); Zhang et al (186); Huang et al (187)
miR-133a; miR-133bEsophageal squamous cell carcinomaInhibition of cell proliferation and cell invasionFSCN1Kano et al (188)
miR-135aProstate cancerInhibition of cell invasion and migrationROCK1, ROCK2Kroiss et al (189)
miR-137Colorectal cancerReduction of invasivenessFMNL2Liang et al (190)
miR-143Non-small cell lung cancerSuppression of cell proliferation; inhibition of cell migration and invasion; induction of apoptosisLimk1Xia et al (191)
miR-145Esophageal squamous cell carcinoma, colon carcinoma, gastric cancer, neuroblastomaInhibition of cell proliferation and cell invasion; reduced tumor proliferation and increased apoptosis; attenuation of gastric cancer cell migratory and invasive abilities in vitro and suppression of the metastatic cascade in vivo; inhibition of the invasion and metastasis of neuroblastoma cellsFSCN1, c-MYC, ERK5, N-cadherin, HIF-2αKano et al (188); Ibrahim et al (91); Gao et al (192); Zhang et al (193)
miR-146a/bProstate, breast cancerInhibition of cell invasion and migrationIRAK1, TRAF6, ROCK1Bhaumik et al (194); Lin et al (195)
miR-148aLiver, lung cancerInhibition of hepatoma cell migration in vitro and pulmonary metastatic colonization in vivoMET/Snail signalingZhang et al (196)
miR-148bBreast cancerInhibition of multiple steps of tumor progression via the regulation of invasion, resistance to anoikis, extravasation, lung metastasis, colonization and chemo-therapeutic responseITGA5, ROCK1, PIK3CA/p110α, NRAS, CSF1Cimino et al (197)
miR-149Breast, lung cancerInhibition of basal-like breast cancer cell migration and invasion in vitro; impairment of lung colonization in vivoRap1a, Rap1bBischoff et al (198)
miR-181bChronic lymphocytic leukemiaInhibition of disease progressionMcl-1, Bcl-2Visone et al (199)
miR-182GlioblastomaInhibition of cell growth and cell differentiationBcl-2L12, c-MET, HIF2AKouri et al (200)
miR-193bBreast cancer, pancreatic ductal adenocarcinomaAlteration of ERα signaling, such as steroid synthesis and downregulation of the ERα receptor; negative regulation of long non-coding oncogenic RNAAKR1C2, AKR1C1, YWHAZ (14-3-3 family protein), RNA MIR31HGLeivonen et al (201); Yang et al (202)
miR-198Hepatocellular carcinomaInhibition of migration and invasionHGF/c-METTan et al (203)
miR-204Neuroblastoma, gliomaStimulation of increased sensitivity to cisplatin treatment and promotion of cell survival; alteration of glioma progression, invasion and migrationTrkBBao et al (204); Xia et al (205)
miR-205Human prostate cancerReduction of cell migration/ invasion through downregulation of protein kinase C epsilonCHN1, ErbB3, E2F1, E2F5, ZEB2, PRKCEGandellini et al (206)
miR-206Breast cancerInhibition of cell invasion and migrationMETChen et al (207)
miR-214Colorectal cancer, liver metastasisSuppression of cell migration and invasion in vitro; inhibition of liver metastasis of colorectal cancer cells in vivoFGFR1Chen et al (208)
miR-218Gastric cancerSuppression of tumor metastasesROBO1Tie et al (209)
miR-296-5pProstate cancerReduction of growth invasion and progressionHMGA1Wei et al (210)
miR-302Breast cancerSensitization of radioresistant breast cancer cells to ionizing radiationAKT1, RAD52Liang et al (99)
miR-302bHepatocellular carcinomaSuppression of cell proliferationEGFRWang et al (211)
miR-335Breast cancerInhibition of cell invasion, migration and metastasisSOX4, PTPRN2, MERTK, TNCTavazoie et al (212); Hurst et al (213)
miR-383 MedulloblastomaControl of cell growthPRDX3Li et al (214)
miR-449Gastric cancer, non-small cell lung cancerInhibition of cell proliferation, inhibition of migration and invasionGMNN, MET, CCNE2, SIRT1Bou Kheir et al (215) Luo et al (216)
miR-493Colon, lung cancerInhibition of the settlement of metastasized colon cancer cells in the liver; promotion of the death of colon cancer cells; suppression of tumor growth, invasion and metastasis in lungsIGFR, E2F1, MKK7Okamoto et al (217); Gu et al (218); Sakai et al (219)
miR-504Hypopharyngeal squamous cell carcinomaInhibition of cancer cells proliferationCDK6Kikkawa et al (220)
miR-520c/373Breast cancerInhibition of cell invasion in vitro and the cell intravasation in vivoRELA, TGFBR2Keklikoglou et al (221)
miR-545Pancreatic ductal adenocarcinoma, lung cancer cellsInhibition of cell growth and proliferationRIG-1, CDK4Song et al (222); Bowen et al (223)
miR-596Oral squamous cell carcinoma (OSCC)Growth inhibitionLGALS3BPEndo et al (96)

3. OncomiRNAs and metastamiRNAs

miRNAs can act as oncogenes and have been demonstrated to play a causal role in the onset and progression of human cancer (oncomiRNAs) (224233). Recent findings have nevertheless identified a subclass of miRNAs whose expression is highly associated with the acquisition of metastatic phenotypes and are referred to as miRs endowed with either metastasis-promoting or tumor suppressor inhibitory activities (213,234,235).

Recent data have revealed that miR-25 may act as an onco-miRNA in osteosarcoma, negatively regulating the protein expression of the cell cycle inhibitor, p27. In agreement with this hypothesis restoring the p27 level in miR-25-over-expressing cells was shown to reverse the enhancing effect of miR-25 on Saos-2 and U2OS cell proliferation (236). In addition a recent study published by Siu et al (237), describes miR-96 as a potential target of therapeutics for metastatic prostate cancer, demonstrating the enhanced effects in cellular growth and invasiveness of miR-96 in cell lines (AC1, AC3 and SC1) derived from prostate-specific, Pten/Tp53 double knockout mice and confirmed in tissue samples from prostate cancer patients. miR-96 acts as an oncomiR and metastamiR through TGF-β/mTOR signaling, promoting bone metastasis and contributing to a reduced survival rate in prostate cancer (237). Furthermore Xia et al (238) demonstrated that the overexpression of miR-1908 significantly decreased the expression of PTEN in glioblastoma cells, one of the most frequently mutated tumor suppressors in human cancer, resulting in an increase in proliferation, migration and invasion. Finally Sachdeva et al (239), found that miR-182 targets multiple genes in lung metastasis and regulates intravasation, thus increasing the number of circulating tumor cells (CTCs). Only the simultaneous restoration of miR-182 target genes decreased the number of metastases in vivo, demonstrating that a single miRNA can regulate the metastasis of primary tumors in vivo by the coordinated regulation of multiple genes. Selected examples of oncomiRNAs and metastamiRNAs are presented in Tables II and III. All these miRNAs act by inhibiting tumor suppressor pathways.

Table II

miRNAs exhibiting oncogenic functions.

Table II

miRNAs exhibiting oncogenic functions.

MicroRNADiseaseBiological effectsTarget mRNA/pathway Authors/(Refs.)
miR-10bHuman esophageal cancer cells, gastric carcinomaPromotion of migration and invasionKLF4Tian et al (240); Wang et al (241)
miR-21Breast, colon, pancreatic, lung, prostate, liver and stomach cancer, chronic lymphocytic leukemia; acute myeloid leukaemia, glioblastoma, neuroblastomaStimulation of cellular proliferation; action on mitochondrial apoptosis tumor-supressive pathways, resisting cell deathPTEN, TPM1, PDCD4, p63, RECK, p53, TGF-βChan et al (242); Zhu et al (230); Frankel et al (231); Volinia et al (233)
miR-23bRenal cancer cellsDownregulation of POX (tumor suppressor), increase in HIF signalingPOXLiu et al (243)
miR-27aProstate cancerIncrease in the expression of AR target genes and prostate cancer cell growthPHBFletcher et al (244)
miR-100Myeloid leukemia, gliomaPromotion of cell differentiation, survival and apoptosisRBSP3, ATMNg et al (245); Zheng et al (246)
miR-125bB-cell leukemiaInduction of cell differentiation and transformationMAP3K11, ARID3BKnackmuss et al (247)
miR-132
miR-212
Pancreatic adenocarcinoma (PDAC)Stimulation of cell proliferation via the β2 adrenergic pathwayRb1Park et al 2011 (248)
miR-155Lymphoma, leukemia, breast, colon, lung, pancreatic, thyroid brain cancer, diffuse large B-cell lymphoma (DLBCL)Causes the constitutive activation of signal transducer and activator of transcription 3, sustaining proliferative signaling, resistance of cell death, activation invasion, migration and metastasisSOCS1, RhoA, FOXO3a, VHLKong et al (249); Jiang et al (250); Czyzyk-Krzeska et al (251); Wang et al (252); Ling et al (253); Musilova et al (254)
miR-17NeuroblastomaMarked increase of in vitro and in vivo tumorigenesisp21, BIMFontana et al (255)
miR-182MelanomaPromotion of melanoma metastasesMITF, FOXO3Segura et al (256)
miR-214Ovarian cancerStimulation of cell survival and cisplatin resistancePTENYang et al (257)
miR-221
miR-222
Atypical teratoid/rhabdoid tumors (ATRT), osteosarcoma, glioma, breast cancer, follicular thyroid carcinoma (FTC), digestive system carcinomaDecrease of cell cycle inhibitor p27Kip1, tumor development and progression by regulating proliferative signaling pathways, altering telomere and telomerase activity, avoiding cell death from tumor suppressors, autophagy and apoptosis, monitoring angiogenesis, supporting epithelial-mesenchymal transition, and even controlling cell-specific function within the microenvironmentp27Kip1, PTEN, KIT, TRPS1, PUMA, PTPμ, FOXO3, PIK3R1, TIMP3, TIMP2, DDIT4, MDM2, ERα, SOCS3, OCS1, HDAC6, ANGPTL2, BBC3, BMF, RECK, PDLIM2, RelA, p57Kip2Zhang et al (258); Garofalo et al (259); Quintavalle et al (260); Chen et al (261); Matsuzaki et al (262)
miR-296Brain tumorsPromotion of angiogenesisHGSWurdinger et al (263)
miR-301Breast cancerPromotion of growth, proliferation, invasion and metastasesFOXF2, BBC3, PTENShi et al (264)
miR-372
miR-373
Testicular tumorsPromotion of tumorigenesis in cooperation with RASLATS2Voorhoeve et al (265)
miR-375Gastric cancerPromotion of carcinogenesisJAK2, PDK1Xu et al (266)
miR-378Breast carcinomaEhnancement of cell survival; reduction of caspase-3 activity; promotion of growth and angiogenesisSufu, Fus-1Lee et al (267)
miR-519aHepatocellular carcinoma, breast cancerPromotion of tumor growth, proliferation; inhibition of apoptosis; tamoxifen resistancePTEN/PI3K/ AKT/FOXF2Tu et al (268); Shao et al (269); Ward et al (270)
miR-675Colorectal cancerOverexpression of H19 (oncofetal non-coding RNA) in cancer tissuesRBTsang et al (271)
miR-1908GlioblastomaPromotion of anchorage independent growth in vitro, increasing of tumor forming potential in vivoPTENXia et al (238)

Table III

miRNAs promoting metastasis.

Table III

miRNAs promoting metastasis.

MicroRNADiseaseBiological effectsTarget mRNA/ pathway Authors/(Refs.)
miR-9Breast, colon cancerPromotion of breast cancer cell motility and invasiveness; enhancement of squamous cell carcinoma CSC expansion and metastasisCDH1, LIFR, α-cateninMa et al (272); Chen et al (273); White et al (274)
miR-10bBreast cancer, glioblastomaPromotion of EMT, migration, invasion and metastasisTP53, PAX6, NOTCH1, HOXD10Ma et al (275); Lin et al (276)
miR-15bPancreatic cancerPromotion of EMTSMURF2Zhang et al (277)
miR-19a/bGastric cancerFacilitation of cell migration, invasion and metastasisMXD1Wu et al (278)
miR-20aCervical, gallbladder cancerFacilitation of cancer cell proliferation and metastasis in vitro and increased tumor growth in vivo; induction of EMTATG7, TIMP2, Smad7Chang et al (279); Zhao et al (280)
miR-21Breast, lung, brain, cervical and colorectal cancer, melanomaDrive to epithelial collective cell migration, invasion, cell metastasis and apoptosis; enhancement of colorectal cancer cell intravasionTPM1, PDCD4, Maspin (SERPINB5), PTEN, PI3K, Sprouty, p53, cyclin D1, FOXO1, FBXO11, TIPE2, MSH2, hTERT, HIF1α, TIMP3, APAF1Zhu et al (230); Dean et al (281); Peacock et al (282); Xu et al (283); Asangani et al (284); Hurst et al (213); Melnik et al (285)
miR-96Prostate cancerBone metastasis, enhanced effects on cellular growth and invasivenessTGF-β/mTOR signalingSiu et al (237)
miR-105Breast cancerDestruction of the integrity of vascular endothelial barriers to promote metastasisZO-1Zhou et al (286)
miR-122Breast cancerPromotion of metastatic colonizationPKM2,Fong et al (287)
miR-135bLung cancerPromotion of cell migration, invasion and metastasisLATS2, TrCP, NDR2, LZTST1Lin et al (288)
miR-181aBreast cancerPromotion of breast cancer metastasisBim/TGF-βTaylor et al (289)
miR-182Gallbladder, sarcoma, lung cancerPromotion of metastasis, circulating tumor cells (CTC); regulation of intravasionCADM1, RSU1, MTSS1, PAI1, TIMP1Qiu et al (290); Sachdeva et al (239)
miR-183Oesophageal carcinomaPromotion of proliferation and invasionPDCD4Ren et al (291)
miR-200sBreast, ovarian cancerActivation of invasion and metastasis (but in other cases inhibition)ZEB1, ZEB2, SIP1, Sec23aKorpal et al (292); Korpal et al (293); Park et al (294); Gregory et al (295)
miR-214Lung adenocarcinoma, melanomaPromotion of migration, invasion and resistance to anoikis of melanoma cells in vitro and the extravasation and lung metastasis formation in vivo; promotion of EMT and metastasisTFAP2C, SufuPenna et al (296); Penna et al (297); Long et al (298)
miR-296-3pProstate cancerPromotion of metastasisICAM1Liu et al (299)
miR-296-5pProstate cancerPromotion of growth and invasion, metastatic progression, and persistence of cancer-initiating cellsNumbl (Klf4 signaling)Vaira et al (300)
miR-362-5pHepatocellular carcinomaPromotion of cell proliferation, migration, invasion in vitro; and tumor growth and metastasis in vivoCYLDNi et al (301)
miR-373Breast cancerDrives EMT and metastasisTXNIPChen et al (302)
miR-520cFibrosarcoma, benign prostatic hyperplasia, glioblastomaPromotion of migration and metastasisMT1-MMPLu et al (303)

4. Mimicking tumor suppressor miRNAs in miRNA replacement therapy

Using the development of anticancer therapies as a representative field of investigation, the therapeutic strategy based on miRNA replacement is targeted to pathological cells which downregulate onco-suppressor miRNAs playing a role in controlling the expression of mRNAs encoding key oncoproteins. The downregulation of these oncogene-targeting miRNAs is clearly the key step for oncogene upregulation leading to tumor onset and progression. Table IV presents selected examples of miRNA replacement therapy in cancer research and treatment (9092,9497,99).

Table IV

miRNA replacement therapy of cancer: selected examples.

Table IV

miRNA replacement therapy of cancer: selected examples.

Tumor typemiRNA targetModulated mRNAEffects following miR treatement Authors/(Refs.)
Lung cancermiR-34aRepression of c-Met, Bcl-2; partial repression of CDK4Block of tumor growthWiggins et al (90)
Colon carcinomamiR-33aPim-1Reduced tumor proliferationIbrahim et al (91)
Colon carcinomamiR-145c-Myc and ERK5Reduced tumor proliferation and increased apoptosisIbrahim et al (91)
Lung cancermiR-let7Negative regulation of the cell cycle oncogenes RAS, MYC and HMGA2Reduction of tumor growthTrang et al (92)
Acute leukemiamiR-27aBax and BadInhibition of cell growth due, at least in part, to increased cellular apoptosisScheibner et al (94)
CML cellsmiR-33aPim-1Decelerated cell proliferationThomas et al (95)
Oral squamous cell carcinoma (OSCC)miR-596LGALS3BPGrowth inhibitionEndo et al (96)
Non-small cell lung adenocarcinomas, A549 cellsmiR-29bCDK6, DNMT3B, MCL-1Inhibition of tumorigenicity in vivoWu et al (97)
Acute myeloid leukemiamiR-29bDownregulation of DNMTs, CDK6, SP1, KIT and FLT3Decreased AML cell growth and impairement of colony formation; longer survival of treated mice; improvement of antileukemic activity of decitabineHuang et al (98)
Laryngeal carcinomamiR-30bp53 via MDM2Antitumor and pro-apoptotic effect in vivo and in vitroLi and Wang (142)
Breast cancermiR-302AKT1 and RAD52Sensitized radioresistant breast cancer cells to ionizing radiationLiang et al (99)

As a first representative example, Fig. 2A presents the major results obtained by Wu et al (97), who reported that the in vivo restoration of miR-29b may represent an option for lung cancer treatment. To demonstrate the efficacy of this strategy, they developed a cationic lipoplexes (LPs)-based carrier that efficiently delivered miR-29b both in vitro and in vivo. LPs containing miR-29b (LP-miR-29b) efficiently delivered miR-29b to A549 cells and reduced the expression of the key target, CDK6. In a xenograft murine model, in which LPs efficiently accumulated at tumor sites, the systemic delivery of LP-miR-29b increased miR-29b expression in tumors, downregulated CDK6 mRNA expression in tumors and, as shown in the upper panels of Fig. 2A, significantly inhibited tumor growth.

A second example of miRNA replacement therapy has been published by Glover et al (304), who reported that miR-7-5p (miR-7) reduces cell proliferation in vitro and induces G1 cell cycle arrest. The systemic miR-7 administration with delivery vesicles reduced adrenocortical carcinoma (ACC) xenograft growth originating from both ACC cell lines and primary ACC cells. As far as the potential mechanisms of action, miR-7 was demonstrated to target Raf-1 proto-oncogene serine/threonine kinase (RAF1). Additionally, miR-7 therapy in vivo led to the inhibition of cyclin dependent kinase 1 (CDK1) (304). Two other methods have also been used to successfully deliver miR-7 in vivo to treat cancer. In a study by Babae et al (305), a miR-7 mimic was systemically delivered using clinically viable, biodegradable, targeted polyamide nanoparticles. This strategy led to the successful inhibition of tumor growth and vascularisation in a glioblastoma xenograft model system. In an earlier study, Wang et al (306) was able to inhibit glioma xenograft growth and metastasis using a plasmid based miR-7 vector systemically delivered by encapsulation in a cationic liposome formulation.

Moreover, Cortez et al (307) revealed a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling. They used a lung cancer xenograft model to demonstrate the therapeutic potential of the systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. The results obtained suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggested that miR-200c, in combination with radiation, may represent an effective therapeutic strategy in the future.

Recently, Wu et al (308) reported that the expression of miR-708-5p suppressed lung cancer invasion and metastasis in vitro and in vivo. In particular, it induces apoptosis and suppresses cell migration by inhibiting the cytoplasmic localization of p21, and also weakens the stem cell-like properties of lung cancer cells. In their study, they present the systemic delivery of the PEI/miR-708-5p complexes for miRNA replacement therapy in a mouse model of lung cancer, demonstrating an efficient antitumor activity with no side-effects.

5. Targeting oncomiRNAs

The effects of therapeutic molecules against miRNAs have been the object of very recent studies, in part summarized in Table V (309316). Of course, the endpoint of the treatment of target cells with molecules against selected miRNAs is the alteration of miRNA-regulated genes. As a first example, Wagenaar et al (317) developed potent and specific single-stranded oligonucleotide inhibitors of miR-21 and used them to verify dependency on miR-21 in a panel of liver cancer cell lines. Treatment with anti-miR-21, but not with a mismatch control anti-miRNA, resulted in the significant derepression of direct targets of miR-21 and led to the loss of viability in the majority of HCC cell lines tested. The robust induction of caspase activity, apoptosis and necrosis was noted in the anti-miR-21-treated HCC cells. Furthermore, the ablation of miR-21 activity resulted in the inhibition of HCC cell migration and in the suppression of clonogenic growth (317).

Table V

AntagomiR-based miRNA targeting therapy of cancer: selected examples.

Table V

AntagomiR-based miRNA targeting therapy of cancer: selected examples.

Cells/tissuesmiRNA targetModulated mRNAEffects following antagomiR treatment Authors/(Refs.)
NeuroblastomamiR-17p21, BIMStrongly increase of in vitro and in vivo tumorigenesisFontana et al (255)
Human glioblastomamiR-27aFOXO3aSuppression of U87 growth in vitro and in vivoGe et al (309)
Malignat astrocytoma cellsmiR-335Daam1Growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenograftsShu et al (310)
Cutaneous squamous cell carcinoma (SCC)miR-155CDC73Decreased cell viability, increased apoptosis, and marked regression of xenografts in nude miceRather et al (311)
NeuroblastomamiR-92DKK3Increases release of the tumor suppressor Dickkopf-3 (DKK3), a secreted protein of the DKK family of Wnt regulatorsHaug et al (312)
GliomamiR-381LRRC4Decreased cell proliferation and tumor growthTang et al (313)
Breast cancermiR-10bHoxd10Suppression of formation of lung metastasesMa et al (314)
Prostate cancer miR-221/miR-222p27Reduction of tumor growthMercatelli et al (315)
Pancreatic cancermiR-221/miR-21SOCS6, SMAD7, CDK6, KLF12, MAPK10Modulation of tumorigenesis, metastasis, and chemotherapy resistance in stem-like cellsZhao et al (316)

In another study, using PNAs as anti-miRNA molecules, Fabani et al (318) targeted miR-155, demonstrating the deregulation of mRNA Bat5, Sfp1 and Jarid2. In our laboratory, Brognara et al analyzed the effects of PNAs targeting miR-221 on breast cancer cells (319). In order to maximize uptake in target cells, a polyarginine-peptide (R8) was conjugated, generating an anti-miR-221 PNA displaying very high affinity for RNA and efficient uptake within target cells without the need for transfection reagents. Targeting miR-221 with this PNA molecule resulted in i) a specific decrease in the hybridization levels of miR-221 measured by RT-qPCR, ii) the upregulation of p27Kip1 mRNA and protein expression, measured by RT-qPCR and western blot analysis, respectively. As regards the in vivo effects of anti-miRNA therapy, Yan et al (320) addressed the potential effects of PNA-anti-miR-21 in vivo on the growth of breast cancer cells. In their experiments, MCF-7 cells treated with PNA-anti-miR-21 or PNA-control were subcutaneously injected into female nude mice and detectable tumor masses were observed in few mice in the MCF/PNA-anti-miR-21 group, while much larger tumors were detected in all mice in the MCF/PNA-control group. Both tumor weight and number showed that MCF/PNA-control cells formed larger tumors more rapidly than MCF/PNA-anti-miR-21 cells in nude mice. As a final example, Cheng et al (57) demonstrated that the PNA anti-miRs with a peptide with a low pH-induced transmembrane structure (pHLIP) target the tumor microenvironment, transport anti-miRs across plasma membranes under acidic conditions, such as those found in solid tumors and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma.

6. MicroRNAs and epithelial-mesenchymal transition

EMT is a powerful process in tumor invasion, metastasis and tumorigenesis, and describes the molecular reprogramming and phenotypic changes that are characterized by a transition from polarized immotile epithelial cells to motile mesenchymal cells (Fig. 3). This process is characterized by the loss of polarity and cell-cell contacts by the differentiated epithelial cells, with deep alterations occurring at the level of tight junctions and desmosomes. The breach of the basement membrane is a following step, leading to the invasion of blood and/or lymphatic vessels by these mesenchymal differentiated cancer cells, which at the end of the process, causes migration, often accompanied by drug resistance (Fig. 3). It is now well-known that several miRNAs are important regulators of EMT. Some of these are miR-7, miR-17/20, miR-22, miR-30, miR-200 and its family members. Most of these miRNAs potentiate EMT, while some well-characterized miRNAs play a suppressive role in EMT. For instance, the metastasis suppressor role of the miR-200 members is strongly associated with the inhibition of EMT. This is well described in the published review by Zhang and Ma (321), and in the studies by Zaravinos et al (322) and Kiesslich et al (323), showing the most recent advances regarding the influence of miRNAs in EMT and the regulatory effects they exert on major signaling pathways in various types of cancer (Fig. 3). In Caski cervical cancer cells, the oncomiR-155 acts as a tumor suppressor and suppresses EGF-induced EMT, decreasing migration/invasion capacities, inhibiting cell proliferation and enhancing the chemosensitivity to DDP in humans (324). Chang et al (279) demonstrated that the overexpression of miR-20a in gallbladder carcinoma cells induced EMT and promoted metastasis via the direct inhibition of Smad7, correlating this miRNA with local invasion, distant metastasis and a poor prognosis in patients with gallbladder carcinoma.

In the ovarian surface epithelium, EMT is considered the key regulator of the post-ovulatory repair process and it can be triggered by a range of environmental stimuli. The aberrant expression of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) in ovarian cancer, and its involvement in the initiation and progression of ovarian cancer have been well demonstrated. The miR-200 family members seem to be strongly associated with EMT and to have a metastasis suppressor role. miRNA signatures can accurately distinguish ovarian cancer from the normal ovary and can be used as diagnostic tools to predict the clinical response to chemotherapy. Recent evidence suggests a growing list of novel miRNAs (miR-187, miR-34a, miR-506, miRNA-138, miR-30c, miR-30d, miR-30e-3p, miR-370 and miR-106a, among others) that are also implicated in ovarian cancer-associated EMT, either enhancing or suppressing it. MicroRNA-based gene therapy provides a prospective antitumor approach for integrated cancer therapy (325).

As regards the molecular targets of EMT-regulating miRNAs, several are known and validated. Among these, transcription factors play a very important role. For instance, Gao et al (326) identified SOX2 as a key player in EMT, by examining the effects of its overexpression. They demonstrated that SOX2-overexpressing Eca-109 cells exhibited an enhanced cell migration/invasion capacity. Moreover, these cells exhibited characteristics of EMT, that is, a significantly suppressed expression of the epithelial cell marker with a concomitant enhancement in the expression of mesenchymal markers. An increased expression of Slug in SOX2-overexpressing cells suggested the involvement of this transcription factor in SOX2-regulated metastasis. Finally, the expression levels of STAT3/HIF-1α were found to be upregulated in SOX2-expressing cells, and the blockade of these transcription factors resulted in the inhibition of Slug expression at both the protein and mRNA level.

Of interest, is also the finding that miR-221/222, which are involved in EMT as positive regulators, can be transcriptionally controlled by Slug. This was demonstrated by Lambertini et al (327), who showed that Slug silencing significantly decreased the level of miR-221, strongly suggesting that miR-221 is a Slug target gene. This was further confirmed by the characterization of a specific region of the miR-221 promoter that is transcriptionally active and is bound by the transcription factor Slug in vivo.

On the other hand, various miRNAs have been reported to directly target EMT-promoting transcription factors. For instance Qiu et al (328) found that miR-139-5p functions as a suppressor of EMT in HCC and metastasis by targeting ZEB1 and ZEB2, and that it may be a therapeutic target for metastatic HCC. In conclusion, miRNAs targeting and miRNA mimicking strategies are both expected to be suitable for the control of EMT.

7. MicroRNAs and neoangiogenesis

A very important step in tumor dissemination and metastasis is neoangiogenesis. This is a very complex process in which several proteins and protein networks participate, for instance interleukin (IL)-8, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietins and matrix metalloproteinases (MMPs). As far as the expression of the IL-8 gene is concerned, the increase in IL-8 gene expression from the healthy brain to low-grade glioma (LGG) can be explained by alterations in the regulatory networks associated with IL-8 gene transcription. Among these, the nuclear factor-κB (NF-κB) network should be proposed, since i) NF-κB is one of the major transcription factors involved in IL-8 gene regulation (329); ii) NF-κB is a marker of glioma onset and progression (330333); iii) miR-16 inhibits glioma cell growth through the suppression of the NF-κB signaling pathway (334). In addition to transcription factors, miRNAs can directly modulate pro-angiogenic factors. For instance, the increased IL-8 gene expression in high-grade glioma (HGG; with respect to LGG) may be associated with decrease of its inhibitory miRNA, miR-93, at least in a subset of HGG patients. The decrease in miR-93 expression in these HGG patients, in addition to IL-8, may lead to the post-transcriptional upregulation of VEGF, monocyte chemoattractant protein-1 (MCP-1) and platelet-derived growth factor (PDGF)-bb, well recognized markers of the late tumor stages of gliomas (335337). However, it should be mentioned that HGG samples are highly heterogeneous with respect to miR-93 levels, suggesting the involvement of multiple regulatory pathways in controlling the level of IL-8 gene expression.

8. Selected examples of miRNA therapeutics: mimicking miR-124

One of the better described examples of tumor suppressor miRNAs is miR-124. This miRNA has been found to play a significant role in several types of cancer (168173,338). Specifically, miR-124 expression is reportedly downregulated in the cells and tissues of esophageal cancer (339), breast cancer (340), renal cell carcinoma (341) and CRC (172). Accordingly, the ectopic expression of miR-124 by target tumor cells inhibits tumor-related parameters in experimental model systems mimicking prostate cancer, medulloblastoma, hepatocellular carcinoma, gastric cancer, glioma, osteosarcoma and CRC.

For instance, Taniguchi et al (164) recently demonstrated that the ectopic expression of miR-124 induced apoptosis and autophagy in colon cancer cells. In addition, miR-124 was demonstrated to target polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of pyruvate kinase muscles 1 and 2 (PKM1 and PKM2), and to induce the switching of PKM isoform expression from PKM2 to PKM1 (164). In addition to this study, Lu et al (342) demonstrated that miR-124a expression was downregulated in human glioma tissues, and that its expression level negatively correlated with the pathological grade of the glioma. The restoration of miR-124a inhibited glioma cell proliferation and invasion in vitro.

Furthermore, they found that miR-124a directly targeted and suppressed IQ motif containing GTPase activating protein 1 (IQGAP1), a well-known regulator of actin dynamics and cell motility (342). Taken together all these data clearly demonstrate that miR-124a is an important tumor suppressor miRNA which is downregulated in cancer cells; accordingly antitumor effects can be achieved following the administration of miR-124, pre-miR-124 or a variety of miR-124 mimics to cancer cells.

Finally, the translational relevance of the role of miR-124 in antitumor drug sensitivity is suggested by the finding that the increased miR-124 expression correlates with an improved breast cancer prognosis, specifically in patients receiving chemotherapy. This finding suggests that miR-124 may potentially be used as a therapeutic agent to improve the efficacy of chemotherapy, including that based on DNA-damaging agents via ATM interactor (ATMIN)- and poly(ADP-ribose) polymerase 1 (PARP1)-mediated mechanisms (343).

9. Selected examples of miRNA therapeutics: mimicking miR-93

A second example of possible miRNA replacement therapy is based on the inhibition of IL-8 and VEGF by the transfection of tumor target cells with pre-miR-93. This was performed in human glioma cell lines (U251 and T98G), as well as on the SK-N-AS neuroblastoma cell line.

The first conclusion of this research activity is that the miRNA, miR-93, is involved in the control of the expression of the IL-8 gene in the glioma U251 and in the neuroblastoma SK-N-AS cell lines (344,345). The effects of these treatments were analyzed by RT-qPCR (looking at the IL-8 mRNA content) or by Bio-plex analysis (looking at IL-8 protein secretion). In addition, Fabbri et al (344) found that the transfection of target cells with pre-miR-93 led to the downregulation of VEGF (see the results depicted in Fig. 4A), suggesting that, as shown in Fig. 4B, miR-93 has effects on the growth of gliomas [by interfering with growth factors, including PDGF, fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-colony stimulating factor(G-CSF)], as well as on neoangiogenesis.

10. Selected examples of anti-miRNA therapeutics: targeting miR-221/222

Gliomas, as other tumors, express miR-221 at high levels, promoting malignant progression through activation of the Akt pathway and the inhibition of p27Kip1 (346349). In addition miR-221 mediates the downregulation of other genes, such as PUMA (258), intercellular adhesion molecule 1 (ICAM-1) (350), TIMP metallopeptidase inhibitor 3 (TIMP3) (351) and phosphatase and tensin homolog (PTEN) (352), and may thus be associated with cancer onset and progression (353). Therefore, miR-221 appears to be a specific target for the treatment of gliomas (354,355). Zhang et al (354) reported that the co-suppression of the miR-221/222 cluster suppressed human glioma cell growth by affecting p27Kip1 expression in vitro and in vivo. In our own laboratory, we have also examined the effects of a PNA against miR-221 and showed that it is able to induce a sharp decrease in miR-221 biological activity. The employed PNA carryed an Arg(8) peptide to facilitate PNA uptake by target cells. Two studies were published on this specific issue. In the first study by Brognara et al (319), we demonstrated that targeting miR-221 induced a sharp increase in the expression of the miR-221 target p27Kip1 mRNA in a breast cancer cell line (319). In a more recent study of ours, Brognara et al (56) demonstrated that the PNA against miR-221 can be internalized by glioma cells when linked to a Arg(8) tail (R8), leading to the inhibition of miR-221 functions, associated with the increased expression of p27Kip1 in U251 and T98G cells. In addition, the expression of another miR-221 target gene, TIMP3, was upregulated following treatment of the T98G cells with R8-PNA-a221. These data support the concept that targeting miR-221 with antagomiR molecules may provide novel options for developing protocols for the treatment of gliomas. This is supported by the finding that the treatment of all the glioma cells lines with R8-PNA-a221 induced the activation of the early apoptotic pathway (56).

11. Combined treatments: targeting multiple miRNAs

Several tumors express upregulated levels of several miRNAs, suggesting that a possible limit to anti-mRNA therapeutics may be the requirement of the co-targeting of several miRNAs to obtain the programmed biological effects. Moreover, an important anti-miRNA strategy may be associated with the obvious need for the co-targeting of different miRNAs belonging to the same miRNA family.

miRNA-replacement therapy

Yang et al (356) found that the co-transfection of miR-137/197 resulted in a reduction in myeloid cell leukemia 1 (MCL-1) protein expression, as well as in the alteration of the expression of apoptosis-related genes, the induction of apoptosis, and in the inhibition of the viability, colony-forming ability and migration ability of multiple myeloma cells. MCL-1 was further validated as a direct target of miR-137/197. Conversely, the overexpression of MCL-1 partially reversed the effects of miR-137/197. Importantly, the in vivo lentiviral-mediated or intratumor delivery of miR-137/197 induced the regression of tumors in murine xenograft models of multiple myeloma (356).

Anti-miRNA therapy

The co-treatment of target cells with antagomiR molecules selective for different miRNAs has been recently described. For instance, Lee et al (357) investigated the role of miRNAs targeting runt related transcription factor 3 (RUNX3) in early tumorigenesis. Under hypoxic conditions, miR-130a and miR-495 are upregulated and target RUNX3 by binding to its 3′-UTR in gastric cancer cells. Using matrigel plug assay, they found that antagomiRs specific for miR-130a and miR-495 significantly reduced angiogenesis in vivo and hypothesized that the co-targeting of miR-130a and miR-495 may prove to be a potential therapeutic strategy with which to recover RUNX3 expression under hypoxic conditions and in early tumorigenesis (357).

In a recent study, Brognara et al (358) treated glioma cell lines with a combined administration of antagomiR-PNAs targeting miR-221 and miR-222. In fact, the same site recognized by miR-221 in the 3′UTR of target mRNAs can be also identified by miR-222, as suggested by predicted molecular interactions using PUMA 3′UTR as a model system. Therefore, the targeting of miR-221 with antagomiRs may not be sufficient to achieve the complete suppression of miR-221 biological activity due to the presence of miR-222 in target cells. Since miR-221 and miR-222 belong to the same transcriptional unit and are, as expected, co-expressed in tumor cell lines (U251, U373 and T98G), Zhang et al (354) determined whether the co-administration of antagomiRs recognizing miR-221 and miR-222 would lead to a more efficient inhibitory activity on miR-221/222 dependent functions. The results obtained demonstrated that the co-suppression of miR-221/222 directly resulted in the upregulation of p27Kip1 in the tested cells and in the inhibtion of cell growth by reducing a G1 to S shift in the cell cycle. Consistently, the knockdown of miR-221/222 through antisense 2′-OME-oligonucleotides increased p27Kip1 expression in mice with U251 glioma subcutaneous tumors and markedly reduced tumor growth in vivo through the upregulation of p27Kip1 (354).

In our own laboratory, we have approached the same issue using PNAs. We have previously reported that a PNA targeting miR-221 can be internalized by glioma cells and exert biological effects on miR-221-dependent functions when it is linked to an octaarginine tail (R8) (56). The major results of the more recent study by Brognara et al (358) are the following: i) R8-conjugated PNAs against miR-221 (R8-PNA-a221) and miR-222 (R8-PNA-a222) exhibit selective biological activity on miR-221 and miR-222; ii) when R8-PNA-a221 and R8-PNA-a222 are singularly administered to glioma cells, the specific inhibition of hybridization to miR-221 and miR-222 is obtained following RT-qPCR analysis; iii) both R8-PNA-a221 and R8-PNA-a222 induce the apoptosis of U251, U373 and T98G glioma cells. Finally, the co-administration of R8-PNA-a221 and R8-PNA-a222 was associated with the most prominent effects of this treatment in inducing apoptosis (see the representative experimental results shown in Fig. 5) (358).

12. Combined treatments: co-administration of antitumor drugs and miRNA therapeutic agents

One of the most interesting results obtained to date using miRNA therapeutics is the formal demonstration that, when used in combination with antitumor drugs, satisfactory therapeutic effects may be achieved (359). This has been demonstrated using both miRNA mimicking approaches, as well as anti-miRNA molecules.

miRNA replacement therapy

Gao et al (360), demonstrated that clear-cell renal cell carcinoma is a tumor type which is highly resistant to treatment and that the miR-200 family was involved in the process of mesenchymal-epithelial transition (MET) during renal development. In their study, evidence was provided to indicate that miR-200c sensitizes ccRCC cells to sorafenib or imatinib to inhibit cell proliferation. The combined application of chemotherapeutic drugs and miR-200c may enhance the efficacy of therapy by promoting both apoptosis and autophagy (360). Another study demonstrating the enhanced effects of the combination of miRNA replacement therapy with antitumor drugs was published by Huang et al (98) with a novel transferrin-conjugated nanoparticle delivery system for synthetic miR-29b (Tf-NP-miR-29b), designed for intervention in the treatment of acute myeloid leukemia (AML). The antileukemic activity of Tf-NP-miR-29b was evaluated by measuring cell proliferation and colony-forming ability in vitro, as well as in vivo using a leukemia mouse model system. Tf-NP-miR-29b treatment significantly downregulated miR-29b targets, such as DNA methyltransferases (DNMTs), CDK6, specificity protein 1 (SP1), KIT and Fms-related tyrosine kinase 3 (FLT3), decreased AML cell growth and impaired colony formation. Mice engrafted with AML cells and then treated with Tf-NP-miR-29b had a significantly longer survival compared with the mice treated with Tf-NP-scramble or free miR-29b. Furthermore, priming AML cells with Tf-NP-miR-29b before treatment with decitabine resulted in a marked decrease in cell viability in vitro and enhanced the antileukemic activity compared to treatment with decitabine alone in vivo, suggesting that miRNA replacement therapy based on the delivery of miR-29b can be proposed for AML therapy also in combination with antitumor drugs.

Moreover, the study by Pogribny et al (361) reported that miR-7 expression directly targeted and significantly inhibited multidrug resistance-associated protein 1 (MPR1), which enhanced sensitivity to cisplatin in cisplatin-resistant breast cancer. Furthermore, an in vitro study by Suto et al (362) demonstrated that miR-7 overexpression enhanced sensitivity to cetuximab and suppressed cell proliferation after treatment with cetuximab in HCT-116 and SW480 cetuximab-resistant CRC cells. Additionally, miR-7 was found to enhance the sensitivity of non-small cell lung cancer (NSCLC) to paclitaxel (PTX) by promoting PTX-induced apoptosis (363). Another recent study demonstrated that the restoration of miR-143 and miR-145 expression in mutant KRAS (HCT116 and SW480) and wild-type KRAS (SW48) colon cancer cells re-sensitized the colon cancer cells to cetuximab by promoting cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) to induce cell death (364).

In our own laboratory, we further analyzed the possible co-admistration of temozolomide (TMZ) and the tumor suppressor pre-miR-124. This was investigated in one neuroblastoma and two glioma cell lines. For miRNA replacement, we employed transfection with pre-miR-124, since miR-124 is a powerful tumor suppressor pro-apoptotic miRNA. In order to demonstrate the activity of the combined treatment, the anti-proliferative and pro-apoptotic effects were analyzed. This set of data confirm that miRNA therapeutics can be successfully combined with chemical treatments to obtain greater effects with low doses of reagents. In conclusion, our data showed that, in addition to the combinations between antitumor drugs and antagomiR-based protocols, interesting results can be obtained by the combination of drugs with miRNA replacement agents (Fabbri et al, unpublished data).

Anti-miRNA therapy

As regards the use of anti-miRNA molecules, Costa et al (365) developed an efficient delivery system for anti-miR-21 oligonucleotides, showing preferential accumulation within brain tumors and efficient miR-21 silencing, which resulted in increased mRNA and protein levels of the miR-21 target RhoB. Decreased tumor cell proliferation and tumor size, as well as enhanced apoptosis and, to a lesser extent, the improvement of animal survival, were observed in glioblastoma tumor-bearing mice upon the systemic delivery of targeted nanoparticle-formulated anti-miR-21 oligonucleotides and exposure to the tyrosine kinase inhibitor, sunitinib (365). Although further studies are warranted to demonstrate a therapeutic benefit in the clinical context, these findings suggest that miRNA modulation by targeted nanoparticles combined with anti-angiogenic chemotherapy may hold promise as an attractive therapeutic approach. Other studies have reported that the downregulation of miR-21 can induce cell apoptosis and reverse drug resistance in cancer treatments; a synergistic antiproliferative and pro-apoptotic activity was obtained using combined treatment, based on anti-miR-21 molecules and temozolomide (366) or doxorubicin (367) in human glioma cell lines. In our own laboratory, we determined whether the treatment of T98G cells with R8-PNA-a221 or R8-PNA-a222 reverses the resistance of the cells to apoptosis induced by TMZ and found that when R8-PNA-a221 and R8-PNA-a222 are co-administered, the reversion of TMZ resistance was much more efficient as opposed to single treatments (358).

A recent study reported the co-delivery of antagomiR-10b and PTX by a liposomal delivery and showed that it efficiently inhibited tumor growth and reduced the incidence of lung metastasis. In fact, antagomiR-10b impeded the migration of 4 T1 cells in vitro, silencing miR-10b and upregulating Hoxd10 both in vitro and in vivo, while PTX elicited potent tumor cell inhibitory effects (368). The same antitumor efficacy and delivery to the tumor site may be achieved by the dual loading of miR-218 mimic (bio-drug) and temozolomide (chemo-drug) using a new delivery nanogel system approach (369).

13. Combining miRNA replacement strategies with anti-miRNAs and siRNA molecules

Xue et al (370) verified the biological activity of novel lung-targeting nanoparticles capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on the activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and the loss of p53 function. The therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored the miR-34a levels in lung tumors, specifically downregulated miR-34a target genes, and attenuated tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved the therapeutic responses as compared to those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared to chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in a model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer (370). A second example is that published by Nishimura et al (371) who first demonstrated that the siRNA-mediated silencing of EphA2, an ovarian cancer oncogene, resulted in the reduction of tumor growth. Second, they presented evidence that the additional inhibition of EphA2 by an miRNA further ‘boosts’ its antitumor effects. They identified miR-520d-3p as a tumor suppressor upstream of EphA2. The restoration of miR-520d-3p prominently decreased EphA2 protein levels, and suppressed tumor growth and migration/invasion both in vitro and in vivo. The dual inhibition of EphA2 in vivo using nanoliposomes loaded with miR-520d-3p and EphA2 siRNA exhibited synergistic antitumor efficiency and greater therapeutic efficacy than either monotherapy alone. These data emphasize the feasibility of combined miRNA-siRNA therapy, and will have broad implications for innovative gene silencing therapies for cancer and other diseases.

A further example in this very exciting field of investigation was reported by Hu et al (372), studying Bcl-2, a prominent member of the Bcl-2 family of proteins that regulate the induction of apoptosis. They investigated the effect of Bcl-2 siRNAs combined with miR-15a oligonucleotides on the growth of Raji cells. Following transfection of these combined reagents, the protein and mRNA levels of Bcl-2 were markedly decreased. The growth of the cells was significantly inhibited compared with the cells transfected with Bcl-2 siRNA or miR-15a alone and the apoptotic rate significantly increased. These results suggest that the combination of Bcl-2 siRNA and miR-15a oligonucleotides increases the apoptosis of Raji cells, and strongly support the concept that the combination of Bcl-2 siRNA and miR-15a may be a useful approach in the treatment of lymphoma.

Finally, an example of possible combined treatment is shown in Fig. 6, which indicates that the co-treatment of U251 cells with PNAs targeting miR-221 or miR-222 in the presence of pre-miR-124 transfection leads to a much higher level of apoptosis as opposed to singularly administered reagents (Fabbri et al, unpublished data).

14. Conclusion

MicroRNA therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, EMT and metastasis. This strategy has been proposed several years ago and is based on the well-recognized fact that miRNAs play a key role in the post-transcriptional control of gene expression by the sequence-selective targeting of mRNAs and are key players in several biological functions and pathological processes, including cancer. In this respect, several studies have conclusively demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. In general, miRNAs able to promote cancer target mRNAs coding for tumor suppressor proteins, whereas miRNAs exhibiting tumor suppressor properties usually target mRNAs coding oncoproteins. This has a very important implication in diagnosis and/or prognosis, including the recent discovery that the pattern of circulating cell-free miRNAs in serum allows us to perform molecular analyses on these non-invasive liquid biopsies. This research field has confirmed that cancer-specific miRNAs are present in extracellular body fluids, and may play a very important role in the crosstalk between cancer cells and surrounding normal cells. Interestingly, the evidence of the presence of miRNAs in serum, plasma and saliva supports their potential as an additional set of biomarkers for cancer.

This review has focused on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA, DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics and plasmids or lentiviral vectors carrying miRNA sequences. However, we should carefully consider that a single miRNA can target several mRNAs (not only tumor-associated mRNAs) and a single mRNA may contain in the 3′UTR sequence several signals for miRNA recognition. In this case, antagomiRNA-based therapy should be designed to target multiple miRNAs. MicroRNA targeting and mimicking is further complicated by the facts that, since their discovery and first characterization, the number of miRNA sequences deposited in the miRBase databases is increasing, and research studies on miRNAs in cancer have confirmed the very high complexity of the networks constituted by miRNAs and RNA targets.

One possible approach includes the combination strategies based on the co-administration of anticancer agents, as shown by the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to drug treatment. In this review, we approached two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is the demonstration that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs.

The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects. This possible combined strategy is in its infancy and very few studies are available in the literature. Proof-of-principle data are presented as examples of possible combined treatments in Fig. 6. Our data indicate that the co-treatment of U251 glioblastoma cells with PNAs targeting miR-221 or miR-222 in the presence of pre-miR-124 transfection leads to a much higher level of apoptosis as opposed to singularly administered reagents. These data further extend the possible combined antitumor treatment based on antitumor drugs and antagomiR-molecules, and present the very novel possibility of combining antagomiR and miRNA replacement therapies.

Acknowledgements

This study was funded by CIB, by COFIN-2009 and by AIRC (IG 13575: peptide nucleic acids targeting oncomiR and tumor-suppressor miRNAs: cancer diagnosis and therapy). EB is supported by an Umberto Veronesi fellowship. We would like to thank the Horizon-2020 ULTRAPLACAD (ULTRA sensitive PLAsmonic devices for early Cancer Diagnosis) n.633937 project for supporting the research on circulating miRNAs as diagnostic tools.

Abbreviations:

miRNAs or miRs

microRNAs

PNA

peptide nucleic acids

CTCs

circulating tumor cells

EMT

epithelial-mesenchymal transition

MET

mesenchymal-epithelial transition

CML

chronic myelogenous leukemia

CRC

colorectal carcinoma

References

1 

Mazière P and Enright AJ: Prediction of microRNA targets. Drug Discov Today. 12:452–458. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Witkos TM, Koscianska E and Krzyzosiak WJ: Practical aspects of microRNA target prediction. Curr Mol Med. 11:93–109. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Ghelani HS, Rachchh MA and Gokani RH: MicroRNAs as newer therapeutic targets: A big hope from a tiny player. J Pharmacol Pharmacother. 3:217–227. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010.PubMed/NCBI

5 

Sun K and Lai EC: Adult-specific functions of animal microRNAs. Nat Rev Genet. 14:535–548. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Chekulaeva M and Filipowicz W: Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr Opin Cell Biol. 21:452–460. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Guo H, Ingolia NT, Weissman JS and Bartel DP: Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 466:835–840. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Cammaerts S, Strazisar M, De Rijk P and Del Favero J: Genetic variants in microRNA genes: Impact on microRNA expression, function, and disease. Front Genet. 6:1862015. View Article : Google Scholar : PubMed/NCBI

9 

Friedländer MR, Lizano E, Houben AJS, Bezdan D, Báñez-Coronel M, Kudla G, Mateu-Huertas E, Kagerbauer B, González J, Chen KC, et al: Evidence for the biogenesis of more than 1,000 novel human microRNAs. Genome Biol. 15:R572014. View Article : Google Scholar : PubMed/NCBI

10 

Cheng WC, Chung IF, Tsai CF, Huang TS, Chen CY, Wang SC, Chang TY, Sun HJ, Chao JY, Cheng CC, et al: YM500v2: a small RNA sequencing (smRNA-seq) database for human cancer miRNome research. Nucleic Acids Res. 43:D862–D867. 2015. View Article : Google Scholar :

11 

Londin E, Loher P, Telonis AG, Quann K, Clark P, Jing Y, Hatzimichael E, Kirino Y, Honda S, Lally M, et al: Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci USA. 112:E1106–E1115. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A and Enright AJ: miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 34:D140–D144. 2006. View Article : Google Scholar :

13 

Kozomara A and Griffiths-Jones S: miRBase: Annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42:D68–D73. 2014. View Article : Google Scholar :

14 

Taccioli C, Fabbri E, Visone R, Volinia S, Calin GA, Fong LY, Gambari R, Bottoni A, Acunzo M, Hagan J, et al: UCbase and miRfunc: A database of ultraconserved sequences and microRNA function. Nucleic Acids Res. 37:D41–D48. 2009. View Article : Google Scholar

15 

Witwer KW: Data submission and quality in microarray-based microRNA profiling. Clin Chem. 59:392–400. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Xie B, Ding Q, Han H and Wu D: miRCancer: A microRNA-cancer association database constructed by text mining on literature. Bioinformatics. 29:638–644. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS and Johnson JM: Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 433:769–773. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Peter ME: Targeting of mRNAs by multiple miRNAs: The next step. Oncogene. 29:2161–2164. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Bianchi N, Finotti A, Ferracin M, Lampronti I, Zuccato C, Breveglieri G, Brognara E, Fabbri E, Borgatti M, Negrini M, et al: Increase of microRNA-210, decrease of raptor gene expression and alteration of mammalian target of rapamycin regulated proteins following mithramycin treatment of human erythroid cells. PLoS One. 10:e01215672015. View Article : Google Scholar : PubMed/NCBI

20 

Subramanian S and Steer CJ: MicroRNAs as gatekeepers of apoptosis. J Cell Physiol. 223:289–298. 2010.PubMed/NCBI

21 

Wang Y and Blelloch R: Cell cycle regulation by MicroRNAs in embryonic stem cells. Cancer Res. 69:4093–4096. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Fabbri E, Borgatti M, Montagner G, Bianchi N, Finotti A, Lampronti I, Bezzerri V, Dechecchi MC, Cabrini G and Gambari R: Expression of microRNA-93 and Interleukin-8 during Pseudomonas aeruginosa-mediated induction of proinflammatory responses. Am J Respir Cell Mol Biol. 50:1144–1155. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Faruq O and Vecchione A: microRNA: Diagnostic perspective. Front Med Lausanne. 2:512015.PubMed/NCBI

24 

Shalaby T, Fiaschetti G, Baumgartner M and Grotzer MA: Significance and therapeutic value of miRNAs in embryonal neural tumors. Molecules. 19:5821–5862. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, et al: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 101:2999–3004. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Palmero EI, de Campos SG, Campos M, de Souza NC, Guerreiro ID, Carvalho AL and Marques MM: Mechanisms and role of microRNA deregulation in cancer onset and progression. Genet Mol Biol. 34:363–370. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ and Wang K: The microRNA spectrum in 12 body fluids. Clin Chem. 56:1733–1741. 2010. View Article : Google Scholar : PubMed/NCBI

28 

Fayyad-Kazan H, Bitar N, Najar M, Lewalle P, Fayyad-Kazan M, Badran R, Hamade E, Daher A, Hussein N, ElDirani R, et al: Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia. J Transl Med. 11:312013. View Article : Google Scholar : PubMed/NCBI

29 

Neviani P and Fabbri M: Exosomic microRNAs in the tumor microenvironment. Front Med Lausanne. 2:472015.PubMed/NCBI

30 

Köberle V, Kronenberger B, Pleli T, Trojan J, Imelmann E, Peveling-Oberhag J, Welker MW, Elhendawy M, Zeuzem S, Piiper A, et al: Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer. 49:3442–3449. 2013. View Article : Google Scholar : PubMed/NCBI

31 

He Y, Lin J, Kong D, Huang M, Xu C, Kim TK, Etheridge A, Luo Y, Ding Y and Wang K: Current state of circulating MicroRNAs as cancer biomarkers. Clin Chem. 61:1138–1155. 2015. View Article : Google Scholar : PubMed/NCBI

32 

Westphal M and Lamszus K: Circulating biomarkers for gliomas. Nat Rev Neurol. 11:556–566. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Yau TO, Wu CW, Dong Y, Tang CM, Ng SS, Chan FK, Sung JJ and Yu J: microRNA-221 and microRNA-18a identification in stool as potential biomarkers for the non-invasive diagnosis of colorectal carcinoma. Br J Cancer. 111:1765–1771. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Cheng H, Zhang L, Cogdell DE, Zheng H, Schetter AJ, Nykter M, Harris CC, Chen K, Hamilton SR and Zhang W: Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS One. 6:e177452011. View Article : Google Scholar : PubMed/NCBI

35 

Czech MP: MicroRNAs as therapeutic targets. N Engl J Med. 354:1194–1195. 2006. View Article : Google Scholar : PubMed/NCBI

36 

Brown BD and Naldini L: Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nat Rev Genet. 10:578–585. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Kota SK and Balasubramanian S: Cancer therapy via modulation of micro RNA levels: A promising future. Drug Discov Today. 15:733–740. 2010. View Article : Google Scholar : PubMed/NCBI

38 

Small EM and Olson EN: Pervasive roles of microRNAs in cardiovascular biology. Nature. 469:336–342. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Bader AG and Lammers P: The Therapeutic Potential of microRNAs. Discovery Technology. 2011.

40 

Rothschild SI: microRNA therapies in cancer. Mol Cell Ther. 2:72014. View Article : Google Scholar : PubMed/NCBI

41 

van Rooij E and Kauppinen S: Development of microRNA therapeutics is coming of age. EMBO Mol Med. 6:851–864. 2014. View Article : Google Scholar : PubMed/NCBI

42 

Orellana EA and Kasinski AL: MicroRNAs in cancer: A historical perspective on the path from discovery to therapy. Cancers (Basel). 7:1388–1405. 2015. View Article : Google Scholar

43 

Berindan-Neagoe I, Monroig PC, Pasculli B and Calin GA: MicroRNAome genome: A treasure for cancer diagnosis and therapy. CA Cancer J Clin. 64:311–336. 2014. View Article : Google Scholar : PubMed/NCBI

44 

Bernardo BC, Ooi JY, Lin RC and McMullen JR: miRNA therapeutics: A new class of drugs with potential therapeutic applications in the heart. Future Med Chem. 7:1771–1792. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Weiler J, Hunziker J and Hall J: Anti-miRNA oligonucleotides (AMOs): Ammunition to target miRNAs implicated in human disease? Gene Ther. 13:496–502. 2006. View Article : Google Scholar

46 

Lu Y, Xiao J, Lin H, Bai Y, Luo X, Wang Z and Yang B: A single anti-microRNA antisense oligodeoxyribonucleotide (AMO) targeting multiple microRNAs offers an improved approach for microRNA interference. Nucleic Acids Res. 37:e242009. View Article : Google Scholar : PubMed/NCBI

47 

Lennox KA and Behlke MA: Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther. 18:1111–1120. 2011. View Article : Google Scholar : PubMed/NCBI

48 

Obad S, dos Santos CO, Petri A, Heidenblad M, Broom O, Ruse C, Fu C, Lindow M, Stenvang J, Straarup EM, et al: Silencing of microRNA families by seed-targeting tiny LNAs. Nat Genet. 43:371–378. 2011. View Article : Google Scholar : PubMed/NCBI

49 

Elmén J, Lindow M, Schütz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjärn M, Hansen HF, Berger U, et al: LNA-mediated microRNA silencing in non-human primates. Nature. 452:896–899. 2008. View Article : Google Scholar : PubMed/NCBI

50 

Stenvang J, Silahtaroglu AN, Lindow M, Elmen J and Kauppinen S: The utility of LNA in microRNA-based cancer diagnostics and therapeutics. Semin Cancer Biol. 18:89–102. 2008. View Article : Google Scholar : PubMed/NCBI

51 

Chabot S, Teissié J and Golzio M: Targeted electro-delivery of oligonucleotides for RNA interference: siRNA and antimiR. Adv Drug Deliv Rev. 81:161–168. 2015. View Article : Google Scholar

52 

Lundin KE, Højland T, Hansen BR, Persson R, Bramsen JB, Kjems J, Koch T, Wengel J and Smith CI: Biological activity and biotechnological aspects of locked nucleic acids. Adv Genet. 82:47–107. 2013. View Article : Google Scholar : PubMed/NCBI

53 

Staedel C, Varon C, Nguyen PH, Vialet B, Chambonnier L, Rousseau B, Soubeyran I, Evrard S, Couillaud F and Darfeuille F: Inhibition of gastric tumor cell growth using seed-targeting LNA as specific, long-lasting MicroRNA inhibitors. Mol Ther Nucleic Acids. 4:e2462015. View Article : Google Scholar : PubMed/NCBI

54 

Avitabile C, Accardo A, Ringhieri P, Morelli G, Saviano M, Montagner G, Fabbri E, Gallerani E, Gambari R and Romanelli A: Incorporation of naked peptide nucleic acids into liposomes leads to fast and efficient delivery. Bioconjug Chem. 26:1533–1541. 2015. View Article : Google Scholar : PubMed/NCBI

55 

Fabbri E, Manicardi A, Tedeschi T, Sforza S, Bianchi N, Brognara E, Finotti A, Breveglieri G, Borgatti M, Corradini R, et al: Modulation of the biological activity of microRNA-210 with peptide nucleic acids (PNAs). ChemMedChem. 6:2192–2202. 2011. View Article : Google Scholar : PubMed/NCBI

56 

Brognara E, Fabbri E, Bazzoli E, Montagner G, Ghimenton C, Eccher A, Cantù C, Manicardi A, Bianchi N, Finotti A, et al: Uptake by human glioma cell lines and biological effects of a peptide-nucleic acids targeting miR-221. J Neurooncol. 118:19–28. 2014. View Article : Google Scholar : PubMed/NCBI

57 

Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, Svoronos A, Braddock DT, Glazer PM, Engelman DM, et al: MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature. 518:107–110. 2015. View Article : Google Scholar

58 

Morris JK, Chomyk A, Song P, Parker N, Deckard S, Trapp BD, Pimplikar SW and Dutta R: Decrease in levels of the evolutionarily conserved microRNA miR-124 affects oligodendrocyte numbers in Zebrafish, Danio rerio. Invert Neurosci. 15:42015. View Article : Google Scholar : PubMed/NCBI

59 

Conte I, Hadfield KD, Barbato S, Carrella S, Pizzo M, Bhat RS, Carissimo A, Karali M, Porter LF, Urquhart J, et al: MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma. Proc Natl Acad Sci USA. 112:E3236–E3245. 2015. View Article : Google Scholar : PubMed/NCBI

60 

Ristori E, Lopez-Ramirez MA, Narayanan A, Hill-Teran G, Moro A, Calvo CF, Thomas JL and Nicoli S: A Dicer-miR-107 interaction regulates biogenesis of specific miRNAs crucial for neurogenesis. Dev Cell. 32:546–560. 2015. View Article : Google Scholar : PubMed/NCBI

61 

Ebert MS, Neilson JR and Sharp PA: MicroRNA sponges: Competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 4:721–726. 2007. View Article : Google Scholar : PubMed/NCBI

62 

Ebert MS and Sharp PA: MicroRNA sponges: Progress and possibilities. RNA. 16:2043–2050. 2010. View Article : Google Scholar : PubMed/NCBI

63 

Kluiver J, Gibcus JH, Hettinga C, Adema A, Richter MK, Halsema N, Slezak-Prochazka I, Ding Y, Kroesen BJ and van den Berg A: Rapid generation of microRNA sponges for microRNA inhibition. PLoS One. 7:e292752012a. View Article : Google Scholar

64 

Kluiver J, Slezak-Prochazka I, Smigielska-Czepiel K, Halsema N, Kroesen BJ and van den Berg A: Generation of miRNA sponge constructs. Methods. 58:113–117. 2012. View Article : Google Scholar : PubMed/NCBI

65 

Li KC, Chang YH, Yeh CL and Hu YC: Healing of osteoporotic bone defects by baculovirus-engineered bone marrow-derived MSCs expressing MicroRNA sponges. Biomaterials. 74:155–166. 2016. View Article : Google Scholar

66 

de Melo Maia B, Ling H, Monroig P, Ciccone M, Soares FA, Calin GA and Rocha RM: Design of a miRNA sponge for the miR-17 miRNA family as a therapeutic strategy against vulvar carcinoma. Mol Cell Probes. 29:420–426. 2015. View Article : Google Scholar : PubMed/NCBI

67 

Tay FC, Lim JK, Zhu H, Hin LC and Wang S: Using artificial microRNA sponges to achieve microRNA loss-of-function in cancer cells. Adv Drug Deliv Rev. 81:117–127. 2015. View Article : Google Scholar

68 

Liu Y, Han Y, Zhang H, Nie L, Jiang Z, Fa P, Gui Y and Cai Z: Synthetic miRNA-mowers targeting miR-183-96-182 cluster or miR-210 inhibit growth and migration and induce apoptosis in bladder cancer cells. PLoS One. 7:e522802012. View Article : Google Scholar

69 

Choi WY, Giraldez AJ and Schier AF: Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430. Science. 318:271–274. 2007. View Article : Google Scholar : PubMed/NCBI

70 

Haraguchi T, Ozaki Y and Iba H: Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 37:e432009. View Article : Google Scholar : PubMed/NCBI

71 

Krol J, Busskamp V, Markiewicz I, Stadler MB, Ribi S, Richter J, Duebel J, Bicker S, Fehling HJ, Schübeler D, et al: Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs. Cell. 141:618–631. 2010. View Article : Google Scholar : PubMed/NCBI

72 

Cassidy JJ, Straughan AJ and Carthew RW: Differential masking of natural genetic variation by miR-9a in Drosophila. Genetics. 202:675–687. 2016. View Article : Google Scholar

73 

Wang Z: The principles of MiRNA-masking antisense oligonucleotides technology. Methods Mol Biol. 676:43–49. 2011. View Article : Google Scholar

74 

Bak RO, Hollensen AK and Mikkelsen JG: Managing microRNAs with vector-encoded decoy-type inhibitors. Mol Ther. 21:1478–1485. 2013. View Article : Google Scholar : PubMed/NCBI

75 

Murakami K and Miyagishi M: Tiny masking locked nucleic acids effectively bind to mRNA and inhibit binding of microRNAs in relation to thermodynamic stability. Biomed Rep. 2:509–512. 2014.PubMed/NCBI

76 

Shin KJ, Wall EA, Zavzavadjian JR, Santat LA, Liu J, Hwang JI, Rebres R, Roach T, Seaman W, Simon MI, et al: A single lentiviral vector platform for microRNA-based conditional RNA interference and coordinated transgene expression. Proc Natl Acad Sci USA. 103:13759–13764. 2006. View Article : Google Scholar : PubMed/NCBI

77 

Askou AL, Aagaard L, Kostic C, Arsenijevic Y, Hollensen AK, Bek T, Jensen TG, Mikkelsen JG and Corydon TJ: Multigenic lentiviral vectors for combined and tissue-specific expression of miRNA- and protein-based antiangiogenic factors. Mol Ther Methods Clin Dev. 2:140642015. View Article : Google Scholar : PubMed/NCBI

78 

Winbanks CE, Beyer C, Hagg A, Qian H, Sepulveda PV and Gregorevic P: miR-206 represses hypertrophy of myogenic cells but not muscle fibers via inhibition of HDAC4. PLoS One. 8:e735892013. View Article : Google Scholar : PubMed/NCBI

79 

Montgomery RL, Yu G, Latimer PA, Stack C, Robinson K, Dalby CM, Kaminski N and van Rooij E: MicroRNA mimicry blocks pulmonary fibrosis. EMBO Mol Med. 6:1347–1356. 2014. View Article : Google Scholar : PubMed/NCBI

80 

Bader AG: miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet. 3:1202012. View Article : Google Scholar : PubMed/NCBI

81 

Kwekkeboom RF, Lei Z, Doevendans PA, Musters RJ and Sluijter JP: Targeted delivery of miRNA therapeutics for cardiovascular diseases: Opportunities and challenges. Clin Sci (Lond). 127:351–365. 2014. View Article : Google Scholar

82 

Sherr CJ: Principles of tumor suppression. Cell. 116:235–246. 2004. View Article : Google Scholar : PubMed/NCBI

83 

Lee YS and Dutta A: The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev. 21:1025–1030. 2007. View Article : Google Scholar : PubMed/NCBI

84 

Mayr C, Hemann MT and Bartel DP: Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science. 315:1576–1579. 2007. View Article : Google Scholar : PubMed/NCBI

85 

Park SM, Shell S, Radjabi AR, Schickel R, Feig C, Boyerinas B, Dinulescu DM, Lengyel E and Peter ME: Let-7 prevents early cancer progression by suppressing expression of the embryonic gene HMGA2. Cell Cycle. 6:2585–2590. 2007. View Article : Google Scholar : PubMed/NCBI

86 

Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P, Petrelli NJ, Dunn SP and Krueger LJ: MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res. 67:9762–9770. 2007. View Article : Google Scholar : PubMed/NCBI

87 

Müller DW and Bosserhoff AK: Integrin beta 3 expression is regulated by let-7a miRNA in malignant melanoma. Oncogene. 27:6698–6706. 2008. View Article : Google Scholar : PubMed/NCBI

88 

Peng Y, Laser J, Shi G, Mittal K, Melamed J, Lee P and Wei JJ: Antiproliferative effects by Let-7 repression of high-mobility group A2 in uterine leiomyoma. Mol Cancer Res. 6:663–673. 2008. View Article : Google Scholar : PubMed/NCBI

89 

Bader AG, Brown D and Winkler M: The promise of microRNA replacement therapy. Cancer Res. 70:7027–7030. 2010. View Article : Google Scholar : PubMed/NCBI

90 

Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D and Bader AG: Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 70:5923–5930. 2010. View Article : Google Scholar : PubMed/NCBI

91 

Ibrahim AF, Weirauch U, Thomas M, Grünweller A, Hartmann RK and Aigner A: MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res. 71:5214–5224. 2011. View Article : Google Scholar : PubMed/NCBI

92 

Trang P, Wiggins JF, Daige CL, Cho C, Omotola M, Brown D, Weidhaas JB, Bader AG and Slack FJ: Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther. 19:1116–1122. 2011. View Article : Google Scholar : PubMed/NCBI

93 

Buechner J, Tømte E, Haug BH, Henriksen JR, Løkke C, Flægstad T and Einvik C: Tumour-suppressor microRNAs let-7 and miR-101 target the proto-oncogene MYCN and inhibit cell proliferation in MYCN-amplified neuroblastoma. Br J Cancer. 105:296–303. 2011. View Article : Google Scholar : PubMed/NCBI

94 

Scheibner KA, Teaboldt B, Hauer MC, Chen X, Cherukuri S, Guo Y, Kelley SM, Liu Z, Baer MR, Heimfeld S, et al: MiR-27a functions as a tumor suppressor in acute leukemia by regulating 14-3-3θ. PLoS One. 7:e508952012. View Article : Google Scholar

95 

Thomas M, Lange-Grünweller K, Weirauch U, Gutsch D, Aigner A, Grünweller A and Hartmann RK: The proto-oncogene Pim-1 is a target of miR-33a. Oncogene. 31:918–928. 2012. View Article : Google Scholar

96 

Endo H, Muramatsu T, Furuta M, Uzawa N, Pimkhaokham A, Amagasa T, Inazawa J and Kozaki K: Potential of tumor-suppressive miR-596 targeting LGALS3BP as a therapeutic agent in oral cancer. Carcinogenesis. 34:560–569. 2013. View Article : Google Scholar

97 

Wu Y, Crawford M, Mao Y, Lee RJ, Davis IC, Elton TS, Lee LJ and Nana-Sinkam SP: Therapeutic delivery of microRNA-29b by cationic lipoplexes for lung cancer. Mol Ther Nucleic Acids. 2:e842013. View Article : Google Scholar : PubMed/NCBI

98 

Huang X, Schwind S, Yu B, Santhanam R, Wang H, Hoellerbauer P, Mims A, Klisovic R, Walker AR, Chan KK, et al: Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: A novel therapeutic strategy in acute myeloid leukemia. Clin Cancer Res. 19:2355–2367. 2013.PubMed/NCBI

99 

Liang Z, Ahn J, Guo D, Votaw JR and Shim H: MicroRNA-302 replacement therapy sensitizes breast cancer cells to ionizing radiation. Pharm Res. 30:1008–1016. 2013. View Article : Google Scholar :

100 

Møller HG, Rasmussen AP, Andersen HH, Johnsen KB, Henriksen M and Duroux M: A systematic review of microRNA in glioblastoma multiforme: Micro-modulators in the mesenchymal mode of migration and invasion. Mol Neurobiol. 47:131–144. 2013. View Article : Google Scholar :

101 

Hershkovitz-Rokah O, Modai S, Pasmanik-Chor M, Toren A, Shomron N, Raanani P, Shpilberg O and Granot G: Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment. Cancer Lett. 360:245–256. 2015. View Article : Google Scholar : PubMed/NCBI

102 

Lee YM, Lee JY, Ho CC, Hong QS, Yu SL, Tzeng CR, Yang PC and Chen HW: miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells. Breast Cancer Res. 13:R1162011. View Article : Google Scholar : PubMed/NCBI

103 

Huang P, Ye B, Yang Y, Shi J and Zhao H: MicroRNA-181 functions as a tumor suppressor in non-small cell lung cancer (NSCLC) by targeting Bcl-2. Tumour Biol. 36:3381–3387. 2015. View Article : Google Scholar

104 

Su R, Lin HS, Zhang XH, Yin XL, Ning HM, Liu B, Zhai PF, Gong JN, Shen C, Song L, et al: MiR-181 family: Regulators of myeloid differentiation and acute myeloid leukemia as well as potential therapeutic targets. Oncogene. 34:3226–3239. 2015. View Article : Google Scholar

105 

Bachetti T, Di Zanni E, Ravazzolo R and Ceccherini I: miR-204 mediates post-transcriptional down-regulation of PHOX2B gene expression in neuroblastoma cells. Biochim Biophys Acta. 1849.1057–1065. 2015.

106 

Fernandez S, Risolino M, Mandia N, Talotta F, Soini Y, Incoronato M, Condorelli G, Banfi S and Verde P: miR-340 inhibits tumor cell proliferation and induces apoptosis by targeting multiple negative regulators of p27 in non-small cell lung cancer. Oncogene. 34:3240–3250. 2015. View Article : Google Scholar

107 

Liu G, Liu Y, Yang Z, Wang J, Li D and Zhang X: Tumor suppressor microRNA-18a regulates tumor proliferation and invasion by targeting TBPL1 in colorectal cancer cells. Mol Med Rep. 12:7643–7648. 2015.PubMed/NCBI

108 

Xishan Z, Ziying L, Jing D and Gang L: MicroRNA-320a acts as a tumor suppressor by targeting BCR/ABL oncogene in chronic myeloid leukemia. Sci Rep. 5:124602015. View Article : Google Scholar : PubMed/NCBI

109 

Zhao Z, Ma X, Sung D, Li M, Kosti A, Lin G, Chen Y, Pertsemlidis A, Hsiao TH and Du L: microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest. RNA Biol. 12:538–554. 2015. View Article : Google Scholar : PubMed/NCBI

110 

Kalinowski FC, Brown RA, Ganda C, Giles KM, Epis MR, Horsham J and Leedman PJ: microRNA-7: A tumor suppressor miRNA with therapeutic potential. Int J Biochem Cell Biol. 54:312–317. 2014. View Article : Google Scholar : PubMed/NCBI

111 

Gu DN, Huang Q and Tian L: The molecular mechanisms and therapeutic potential of microRNA-7 in cancer. Expert Opin Ther Targets. 19:415–426. 2015. View Article : Google Scholar

112 

Nohata N, Hanazawa T, Enokida H and Seki N: microRNA-1/133a and microRNA-206/133b clusters: Dysregulation and functional roles in human cancers. Oncotarget. 3:9–21. 2012.PubMed/NCBI

113 

Hudson RS, Yi M, Esposito D, Watkins SK, Hurwitz AA, Yfantis HG, Lee DH, Borin JF, Naslund MJ, Alexander RB, et al: MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer. Nucleic Acids Res. 40:3689–3703. 2012. View Article : Google Scholar : PubMed/NCBI

114 

Chang YS, Chen WY, Yin JJ, Sheppard-Tillman H, Huang J and Liu YN: EGF receptor pomotes prostate cancer bone metastasis by downregulating miR-1 and activating TWIST1. Cancer Res. 75:3077–3086. 2015. View Article : Google Scholar : PubMed/NCBI

115 

Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, Jiang L, Zhang Y and Dou J: MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells. 32:2858–2868. 2014a. View Article : Google Scholar

116 

Okuda H, Xing F, Pandey PR, Sharma S, Watabe M, Pai SK, Mo YY, Iiizumi-Gairani M, Hirota S, Liu Y, et al: miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4. Cancer Res. 73:1434–1444. 2013. View Article : Google Scholar : PubMed/NCBI

117 

Zhou X, Hu Y, Dai L, Wang Y, Zhou J, Wang W, Di W and Qiu L: MicroRNA-7 inhibits tumor metastasis and reverses epithelial-mesenchymal transition through AKT/ERK1/2 inactivation by targeting EGFR in epithelial ovarian cancer. PLoS One. 9:e967182014. View Article : Google Scholar : PubMed/NCBI

118 

Dangi-Garimella S, Yun J, Eves EM, Newman M, Erkeland SJ, Hammond SM, Minn AJ and Rosner MR: Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J. 28:347–358. 2009. View Article : Google Scholar : PubMed/NCBI

119 

Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, et al: Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64:3753–3756. 2004. View Article : Google Scholar : PubMed/NCBI

120 

Shi XB, Tepper CG and deVere White RW: Cancerous miRNAs and their regulation. Cell Cycle. 7:1529–1538. 2008. View Article : Google Scholar : PubMed/NCBI

121 

Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D and Slack FJ: RAS is regulated by the let-7 microRNA family. Cell. 120:635–647. 2005. View Article : Google Scholar : PubMed/NCBI

122 

Zheng L, Qi T, Yang D, Qi M, Li D, Xiang X, Huang K and Tong Q: microRNA-9 suppresses the proliferation, invasion and metastasis of gastric cancer cells through targeting cyclin D1 and Ets1. PLoS One. 8:e557192013. View Article : Google Scholar : PubMed/NCBI

123 

Aqeilan RI, Calin GA and Croce CM: miR-15a and miR-16-1 in cancer: Discovery, function and future perspectives. Cell Death Differ. 17:215–220. 2010. View Article : Google Scholar

124 

Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, et al: Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 99:15524–15529. 2002. View Article : Google Scholar

125 

Pekarsky Y and Croce CM: Role of miR-15/16 in CLL. Cell Death Differ. 22:6–11. 2015. View Article : Google Scholar

126 

Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, D'Urso L, Pagliuca A, Biffoni M, Labbaye C, et al: The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med. 14:1271–1277. 2008. View Article : Google Scholar : PubMed/NCBI

127 

Kang W, Tong JH, Lung RW, Dong Y, Zhao J, Liang Q, Zhang L, Pan Y, Yang W, Pang JC, et al: Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer. 14:522015. View Article : Google Scholar : PubMed/NCBI

128 

Chen F, Chen L, He H, Huang W, Zhang R, Li P, et al: Up-regulation of microRNA-16 in glioblastoma inhibits the function of endothelial cells and tumor angiogenesis by targeting Bmi-1. Anticancer Agents Med Chem. 2015.

129 

Humphreys KJ, McKinnon RA and Michael MZ: miR-18a inhibits CDC42 and plays a tumour suppressor role in colorectal cancer cells. PLoS One. 9:e1122882014. View Article : Google Scholar : PubMed/NCBI

130 

Zoni E, van der Horst G, van de Merbel AF, Chen L, Rane JK, Pelger RC, Collins AT, Visakorpi T, Snaar-Jagalska BE, Maitland NJ, et al: miR-25 modulates invasiveness and dissemination of human prostate cancer cells via regulation of αv- and α6 integrin expression. Cancer Res. 75:2326–2336. 2015. View Article : Google Scholar : PubMed/NCBI

131 

Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, Chen CJ, Hildesheim A, Sugden B and Ahlquist P: MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci USA. 105:5874–5878. 2008. View Article : Google Scholar : PubMed/NCBI

132 

Ugalde AP, Ramsay AJ, de la Rosa J, Varela I, Mariño G, Cadiñanos J, Lu J, Freije JM and López-Otín C: Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53. EMBO J. 30:2219–2232. 2011. View Article : Google Scholar : PubMed/NCBI

133 

Garzon R, Heaphy CE, Havelange V, Fabbri M, Volinia S, Tsao T, Zanesi N, Kornblau SM, Marcucci G, Calin GA, et al: MicroRNA 29b functions in acute myeloid leukemia. Blood. 114:5331–5341. 2009a. View Article : Google Scholar

134 

Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E, Schwind S, Pang J, Yu J, Muthusamy N, et al: MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 113:6411–6418. 2009b. View Article : Google Scholar

135 

Kapinas K, Kessler CB and Delany AM: miR-29 suppression of osteonectin in osteoblasts: Regulation during differentiation and by canonical Wnt signaling. J Cell Biochem. 108:216–224. 2009. View Article : Google Scholar : PubMed/NCBI

136 

Mott JL, Kobayashi S, Bronk SF and Gores GJ: miR-29 regulates Mcl-1 protein expression and apoptosis. Oncogene. 26:6133–6140. 2007. View Article : Google Scholar : PubMed/NCBI

137 

Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, et al: MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA. 104:15805–15810. 2007. View Article : Google Scholar : PubMed/NCBI

138 

Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH and Zhuang SM: Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology. 51:836–845. 2010.

139 

Filkowski JN, Ilnytskyy Y, Tamminga J, Koturbash I, Golubov A, Bagnyukova T, Pogribny IP and Kovalchuk O: Hypomethylation and genome instability in the germline of exposed parents and their progeny is associated with altered miRNA expression. Carcinogenesis. 31:1110–1115. 2010. View Article : Google Scholar

140 

Wang Y, Zhang X, Li H, Yu J and Ren X: The role of miRNA-29 family in cancer. Eur J Cell Biol. 92:123–128. 2013. View Article : Google Scholar : PubMed/NCBI

141 

Hu W, Dooley J, Chung SS, Chandramohan D, Cimmino L, Mukherjee S, Mason CE, de Strooper B, Liston A and Park CY: miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a. Blood. 125:2206–2216. 2015. View Article : Google Scholar : PubMed/NCBI

142 

Li L and Wang B: Overexpression of microRNA-30b improves adenovirus-mediated p53 cancer gene therapy for laryngeal carcinoma. Int J Mol Sci. 15:19729–19740. 2014. View Article : Google Scholar : PubMed/NCBI

143 

Hou C, Sun B, Jiang Y, Zheng J, Yang N, Ji C, Liang Z, Shi J, Zhang R, Liu Y, et al: MicroRNA-31 inhibits lung adenocarcinoma stem-like cells via down-regulation of MET-PI3K-Akt signaling pathway. Anticancer Agents Med Chem. 16:501–518. 2016. View Article : Google Scholar

144 

Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szász AM, Wang ZC, Brock JE, Richardson AL and Weinberg RA: A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell. 137:1032–1046. 2009. View Article : Google Scholar : PubMed/NCBI

145 

Sossey-Alaoui K, Downs-Kelly E, Das M, Izem L, Tubbs R and Plow EF: WAVE3, an actin remodeling protein, is regulated by the metastasis suppressor microRNA, miR-31, during the invasion-metastasis cascade. Int J Cancer. 129:1331–1343. 2011. View Article : Google Scholar :

146 

Lin Y, Liu AY, Fan C, Zheng H, Li Y, Zhang C, Wu S, Yu D, Huang Z, Liu F, et al: MicroRNA-33b inhibits breast cancer metastasis by targeting HMGA2, SALL4 and Twist1. Sci Rep. 5:99952015. View Article : Google Scholar : PubMed/NCBI

147 

Xu N, Li Z, Yu Z, Yan F, Liu Y, Lu X and Yang W: MicroRNA-33b suppresses migration and invasion by targeting c-Myc in osteosarcoma cells. PLoS One. 9:e1153002014. View Article : Google Scholar : PubMed/NCBI

148 

He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, et al: A microRNA component of the p53 tumour suppressor network. Nature. 447:1130–1134. 2007. View Article : Google Scholar : PubMed/NCBI

149 

Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, et al: p53-mediated activation of miRNA34 candidate tumorsuppressor genes. Curr Biol. 17:1298–1307. 2007. View Article : Google Scholar : PubMed/NCBI

150 

Fujita Y, Kojima K, Hamada N, Ohhashi R, Akao Y, Nozawa Y, Deguchi T and Ito M: Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. Biochem Biophys Res Commun. 377:114–119. 2008. View Article : Google Scholar : PubMed/NCBI

151 

Leucci E, Cocco M, Onnis A, De Falco G, van Cleef P, Bellan C, van Rijk A, Nyagol J, Byakika B, Lazzi S, et al: MYC translocation-negative classical Burkitt lymphoma cases: An alternative pathogenetic mechanism involving miRNA deregulation. J Pathol. 216:440–450. 2008. View Article : Google Scholar : PubMed/NCBI

152 

Saito Y, Nakaoka T and Saito H: microRNA-34a as a therapeutic agent against human cancer. J Clin Med. 4:1951–1959. 2015. View Article : Google Scholar : PubMed/NCBI

153 

Wei JS, Song YK, Durinck S, Chen QR, Cheuk AT, Tsang P, Zhang Q, Thiele CJ, Slack A, Shohet J, et al: The MYCN oncogene is a direct target of miR-34a. Oncogene. 27:5204–5213. 2008. View Article : Google Scholar : PubMed/NCBI

154 

Yamakuchi M, Ferlito M and Lowenstein CJ: miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA. 105:13421–13426. 2008. View Article : Google Scholar : PubMed/NCBI

155 

Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Körner H, Knyazev P, Diebold J and Hermeking H: Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle. 7:2591–2600. 2008. View Article : Google Scholar : PubMed/NCBI

156 

Yang S, Li Y, Gao J, Zhang T, Li S, Luo A, Chen H, Ding F, Wang X and Liu Z: MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene. 32:4294–4303. 2013. View Article : Google Scholar

157 

Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, Deng Y, Zhao J, Jiang S, Yuan Y, et al: TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 22:291–303. 2012. View Article : Google Scholar : PubMed/NCBI

158 

Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, et al: The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 17:211–215. 2011. View Article : Google Scholar : PubMed/NCBI

159 

Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang TC, Xie XJ, He L, Mangala LS, Lopez-Berestein G, et al: miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature. 512:431–435. 2014. View Article : Google Scholar : PubMed/NCBI

160 

Wang LG, Ni Y, Su BH, Mu XR, Shen HC and Du JJ: MicroRNA-34b functions as a tumor suppressor and acts as a nodal point in the feedback loop with Met. Int J Oncol. 42:957–962. 2013.PubMed/NCBI

161 

Yu Z, Kim J, He L, Creighton CJ, Gunaratne PH, Hawkins SM and Matzuk MM: Functional analysis of miR-34c as a putative tumor suppressor in high-grade serous ovarian cancer. Biol Reprod. 91:1132014. View Article : Google Scholar : PubMed/NCBI

162 

Liu XY, Liu ZJ, He H, Zhang C and Wang YL: MicroRNA-101-3p suppresses cell proliferation, invasion and enhances chemotherapeutic sensitivity in salivary gland adenoid cystic carcinoma by targeting Pim-1. Am J Cancer Res. 5:3015–3029. 2015.PubMed/NCBI

163 

Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, Huang Y, Chen HC, Lee CH, Tsai TF, et al: MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 122:2884–2897. 2012. View Article : Google Scholar : PubMed/NCBI

164 

Taniguchi K, Sugito N, Kumazaki M, Shinohara H, Yamada N, Nakagawa Y, Ito Y, Otsuki Y, Uno B, Uchiyama K, et al: MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer. Cancer Lett. 363:17–27. 2015. View Article : Google Scholar : PubMed/NCBI

165 

Huang TC, Chang HY, Chen CY, Wu PY, Lee H, Liao YF, Hsu WM, Huang HC and Juan HF: Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR. FEBS Lett. 585:3582–3586. 2011. View Article : Google Scholar : PubMed/NCBI

166 

Kato T, Enomoto A, Watanabe T, Haga H, Ishida S, Kondo Y, Furukawa K, Urano T, Mii S, Weng L, et al: TRIM27/MRTF-B-dependent integrin β1 expression defines leading cells in cancer cell collectives. Cell Rep. 7:1156–1167. 2014. View Article : Google Scholar : PubMed/NCBI

167 

Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, Bian XW, Guan XY, Lin MC, Zeng YX, et al: The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 61:278–289. 2012. View Article : Google Scholar

168 

Wang X, Wu Q, Xu B, Wang P, Fan W, Cai Y, Gu X and Meng F: miR-124 exerts tumor suppressive functions on the cell proliferation, motility and angiogenesis of bladder cancer by fine-tuning UHRF1. FEBS J. 282:4376–4388. 2015. View Article : Google Scholar : PubMed/NCBI

169 

Zhang C, Hu Y, Wan J and He H: MicroRNA-124 suppresses the migration and invasion of osteosarcoma cells via targeting ROR2-mediated non-canonical Wnt signaling. Oncol Rep. 34:2195–2201. 2015.PubMed/NCBI

170 

Sun Y, Ai X, Shen S and Lu S: NF-κB-mediated miR-124 suppresses metastasis of non-small-cell lung cancer by targeting MYO10. Oncotarget. 6:8244–8254. 2015a. View Article : Google Scholar

171 

Sun Y, Luo ZM, Guo XM, Su DF and Liu X: An updated role of microRNA-124 in central nervous system disorders: A review. Front Cell Neurosci. 9:1932015b. View Article : Google Scholar

172 

Chen Z, Liu S, Tian L, Wu M, Ai F, Tang W, Zhao L, Ding J, Zhang L and Tang A: miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1. Oncotarget. 6:38139–38150. 2015.PubMed/NCBI

173 

Zhang Y, Li H, Han J and Zhang Y: Down-regulation of microRNA-124 is correlated with tumor metastasis and poor prognosis in patients with lung cancer. Int J Clin Exp Pathol. 8:1967–1972. 2015.PubMed/NCBI

174 

Cowden Dahl KD, Dahl R, Kruichak JN and Hudson LG: The epidermal growth factor receptor responsive miR-125a represses mesenchymal morphology in ovarian cancer cells. Neoplasia. 11:1208–1215. 2009. View Article : Google Scholar : PubMed/NCBI

175 

Fan Z, Cui H, Xu X, Lin Z, Zhang X, Kang L, Han B, Meng J, Yan Z, Yan X, et al: MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3. Oncotarget. 6:25266–25280. 2015. View Article : Google Scholar : PubMed/NCBI

176 

Sun Y, Bai Y, Zhang F, Wang Y, Guo Y and Guo L: miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem Biophys Res Commun. 391:1483–1489. 2010. View Article : Google Scholar

177 

Xiong Y, Kotian S, Zeiger MA, Zhang L and Kebebew E: miR-126-3p inhibits thyroid cancer cell growth and metastasis, and is associated with aggressive thyroid cancer. PLoS One. 10:e01304962015. View Article : Google Scholar : PubMed/NCBI

178 

Wang CZ, Yuan P and Li Y: MiR-126 regulated breast cancer cell invasion by targeting ADAM9. Int J Clin Exp Pathol. 8:6547–6553. 2015.PubMed/NCBI

179 

Wen Q, Zhao J, Bai L, Wang T, Zhang H and Ma Q: miR-126 inhibits papillary thyroid carcinoma growth by targeting LRP6. Oncol Rep. 34:2202–2210. 2015.PubMed/NCBI

180 

Jiang L, He A, Zhang Q and Tao C: miR-126 inhibits cell growth, invasion, and migration of osteosarcoma cells by downregulating ADAM-9. Tumour Biol. 35:12645–12654. 2014. View Article : Google Scholar : PubMed/NCBI

181 

Du C, Lv Z, Cao L, Ding C, Gyabaah OA, Xie H, Zhou L, Wu J and Zheng S: MiR-126-3p suppresses tumor metastasis and angiogenesis of hepatocellular carcinoma by targeting LRP6 and PIK3R2. J Transl Med. 12:2592014. View Article : Google Scholar : PubMed/NCBI

182 

Zhang Y, Wang X, Xu B, Wang B, Wang Z, Liang Y, Zhou J, Hu J and Jiang B: Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer. Oncol Rep. 30:1976–1984. 2013.PubMed/NCBI

183 

Png KJ, Halberg N, Yoshida M and Tavazoie SF: A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature. 481:190–194. 2011. View Article : Google Scholar : PubMed/NCBI

184 

Shi ZM, Wang J, Yan Z, You YP, Li CY, Qian X, Yin Y, Zhao P, Wang YY, Wang XF, et al: MiR-128 inhibits tumor growth and angiogenesis by targeting p70S6K1. PLoS One. 7:e327092012. View Article : Google Scholar : PubMed/NCBI

185 

Wuchty S, Arjona D, Li A, Kotliarov Y, Walling J, Ahn S, Zhang A, Maric D, Anolik R, Zenklusen JC, et al: Prediction of associations between microRNAs and gene expression in glioma biology. PLoS One. 6:e146812011. View Article : Google Scholar : PubMed/NCBI

186 

Zhang Y, Chao T, Li R, Liu W, Chen Y, Yan X, Gong Y, Yin B, Liu W, Qiang B, et al: MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med Berl. 87:43–51. 2009. View Article : Google Scholar

187 

Huang CY, Huang XP, Zhu JY, Chen ZG, Li XJ, Zhang XH, Huang S, He JB, Lian F, Zhao YN, et al: miR-128-3p suppresses hepatocellular carcinoma proliferation by regulating PIK3R1 and is correlated with the prognosis of HCC patients. Oncol Rep. 33:2889–2898. 2015.PubMed/NCBI

188 

Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, Chiyomaru T, Enokida H, Nakagawa M and Matsubara H: miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 127:2804–2814. 2010. View Article : Google Scholar

189 

Kroiss A, Vincent S, Decaussin-Petrucci M, Meugnier E, Viallet J, Ruffion A, Chalmel F, Samarut J and Allioli N: Androgen-regulated microRNA-135a decreases prostate cancer cell migration and invasion through downregulating ROCK1 and ROCK2. Oncogene. 34:2846–2855. 2015. View Article : Google Scholar

190 

Liang L, Li X, Zhang X, Lv Z, He G, Zhao W, Ren X, Li Y, Bian X, Liao W, et al: MicroRNA-137, an HMGA1 target, suppresses colorectal cancer cell invasion and metastasis in mice by directly targeting FMNL2. Gastroenterology. 144:624–635.e4. 2013. View Article : Google Scholar

191 

Xia H, Sun S, Wang B, Wang T, Liang C, Li G, Huang C, Qi D and Chu X: miR-143 inhibits NSCLC cell growth and metastasis by targeting Limk1. Int J Mol Sci. 15:11973–11983. 2014. View Article : Google Scholar : PubMed/NCBI

192 

Gao P, Xing AY, Zhou GY, Zhang TG, Zhang JP, Gao C, Li H and Shi DB: The molecular mechanism of microRNA-145 to suppress invasion-metastasis cascade in gastric cancer. Oncogene. 32:491–501. 2013. View Article : Google Scholar

193 

Zhang H, Pu J, Qi T, Qi M, Yang C, Li S, Huang K, Zheng L and Tong Q: MicroRNA-145 inhibits the growth, invasion, metastasis and angiogenesis of neuroblastoma cells through targeting hypoxia-inducible factor 2 alpha. Oncogene. 33:387–397. 2014. View Article : Google Scholar

194 

Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J and Benz CC: Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 27:5643–5647. 2008. View Article : Google Scholar : PubMed/NCBI

195 

Lin SL, Chiang A, Chang D and Ying SY: Loss of miR-146a function in hormone-refractory prostate cancer. RNA. 14:417–424. 2008. View Article : Google Scholar : PubMed/NCBI

196 

Zhang JP, Zeng C, Xu L, Gong J, Fang JH and Zhuang SM: MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene. 33:4069–4076. 2014. View Article : Google Scholar

197 

Cimino D, De Pittà C, Orso F, Zampini M, Casara S, Penna E, Quaglino E, Forni M, Damasco C, Pinatel E, et al: miR148b is a major coordinator of breast cancer progression in a relapse-associated microRNA signature by targeting ITGA5, ROCK1, PIK3CA, NRAS, and CSF1. FASEB J. 27:1223–1235. 2013. View Article : Google Scholar

198 

Bischoff A, Huck B, Keller B, Strotbek M, Schmid S, Boerries M, Busch H, Müller D and Olayioye MA: miR149 functions as a tumor suppressor by controlling breast epithelial cell migration and invasion. Cancer Res. 74:5256–5265. 2014. View Article : Google Scholar : PubMed/NCBI

199 

Visone R, Veronese A, Rassenti LZ, Balatti V, Pearl DK, Acunzo M, Volinia S, Taccioli C, Kipps TJ and Croce CM: miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood. 118:3072–3079. 2011. View Article : Google Scholar : PubMed/NCBI

200 

Kouri FM, Hurley LA, Daniel WL, Day ES, Hua Y, Hao L, Peng CY, Merkel TJ, Queisser MA, Ritner C, et al: miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes Dev. 29:732–745. 2015. View Article : Google Scholar : PubMed/NCBI

201 

Leivonen SK, Rokka A, Ostling P, Kohonen P, Corthals GL, Kallioniemi O and Perälä M: Identification of miR-193b targets in breast cancer cells and systems biological analysis of their functional impact. Mol Cell Proteomics. 10:M110.0053222011. View Article : Google Scholar : PubMed/NCBI

202 

Yang H, Liu P, Zhang J, Peng X, Lu Z, Yu S, Meng Y, Tong WM and Chen J: Long noncoding RNA MIR31HG exhibits oncogenic property in pancreatic ductal adenocarcinoma and is negatively regulated by miR-193b. Oncogene. Nov 9–2015.(Epub ahead of print). View Article : Google Scholar

203 

Tan S, Li R, Ding K, Lobie PE and Zhu T: miR-198 inhibits migration and invasion of hepatocellular carcinoma cells by targeting the HGF/c-MET pathway. FEBS Lett. 585:2229–2234. 2011. View Article : Google Scholar : PubMed/NCBI

204 

Bao W, Wang HH, Tian FJ, He XY, Qiu MT, Wang JY, Zhang HJ, Wang LH and Wan XP: A TrkB-STAT3-miR-204-5p regulatory circuitry controls proliferation and invasion of endometrial carcinoma cells. Mol Cancer. 12:1552013. View Article : Google Scholar : PubMed/NCBI

205 

Xia Z, Liu F, Zhang J and Liu L: Decreased expression of MiRNA-204-5p contributes to glioma progression and promotes glioma cell growth, migration and invasion. PLoS One. 10:e01323992015. View Article : Google Scholar : PubMed/NCBI

206 

Gandellini P, Folini M, Longoni N, Pennati M, Binda M, Colecchia M, Salvioni R, Supino R, Moretti R, Limonta P, et al: miR-205 exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res. 69:2287–2295. 2009. View Article : Google Scholar : PubMed/NCBI

207 

Chen QY, Jiao DM, Yan L, Wu YQ, Hu HZ, Song J, Yan J, Wu LJ, Xu LQ and Shi JG: Comprehensive gene and microRNA expression profiling reveals miR-206 inhibits MET in lung cancer metastasis. Mol Biosyst. 11:2290–2302. 2015. View Article : Google Scholar : PubMed/NCBI

208 

Chen DL, Wang ZQ, Zeng ZL, Wu WJ, Zhang DS, Luo HY, Wang F, Qiu MZ, Wang DS, Ren C, et al: Identification of microRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression. Hepatology. 60:598–609. 2014. View Article : Google Scholar : PubMed/NCBI

209 

Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y, et al: MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 6:e10008792010. View Article : Google Scholar : PubMed/NCBI

210 

Wei JJ, Wu X, Peng Y, Shi G, Basturk O, Yang X, Daniels G, Osman I, Ouyang J, Hernando E, et al: Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion. Clin Cancer Res. 17:1297–1305. 2011. View Article : Google Scholar :

211 

Wang L, Yao J, Shi X, Hu L, Li Z, Song T and Huang C: MicroRNA-302b suppresses cell proliferation by targeting EGFR in human hepatocellular carcinoma SMMC-7721 cells. BMC Cancer. 13:4482013. View Article : Google Scholar : PubMed/NCBI

212 

Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL and Massagué J: Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 451:147–152. 2008. View Article : Google Scholar : PubMed/NCBI

213 

Hurst DR, Edmonds MD and Welch DR: Metastamir: The field of metastasis-regulatory microRNA is spreading. Cancer Res. 69:7495–7498. 2009. View Article : Google Scholar : PubMed/NCBI

214 

Li KK, Pang JC, Lau KM, Zhou L, Mao Y, Wang Y, Poon WS and Ng HK: MiR-383 is downregulated in medulloblastoma and targets peroxiredoxin 3 (PRDX3). Brain Pathol. 23:413–425. 2013. View Article : Google Scholar

215 

Bou Kheir T, Futoma-Kazmierczak E, Jacobsen A, Krogh A, Bardram L, Hother C, Grønbæk K, Federspiel B, Lund AH and Friis-Hansen L: miR-449 inhibits cell proliferation and is down-regulated in gastric cancer. Mol Cancer. 10:292011. View Article : Google Scholar : PubMed/NCBI

216 

Luo W, Huang B, Li Z, Li H, Sun L, Zhang Q, Qiu X and Wang E: MicroRNA-449a is downregulated in non-small cell lung cancer and inhibits migration and invasion by targeting c-Met. PLoS One. 8:e647592013. View Article : Google Scholar : PubMed/NCBI

217 

Okamoto K, Ishiguro T, Midorikawa Y, Ohata H, Izumiya M, Tsuchiya N, Sato A, Sakai H and Nakagama H: miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver. EMBO J. 31:1752–1763. 2012. View Article : Google Scholar : PubMed/NCBI

218 

Gu Y, Cheng Y, Song Y, Zhang Z, Deng M, Wang C, Zheng G and He Z: MicroRNA-493 suppresses tumor growth, invasion and metastasis of lung cancer by regulating E2F1. PLoS One. 9:e1026022014. View Article : Google Scholar : PubMed/NCBI

219 

Sakai H1, Sato A, Aihara Y, Ikarashi Y, Midorikawa Y, Kracht M, Nakagama H and Okamoto K: MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells. Cancer Sci. 105:425–430. 2014. View Article : Google Scholar : PubMed/NCBI

220 

Kikkawa N, Kinoshita T, Nohata N, Hanazawa T, Yamamoto N, Fukumoto I, Chiyomaru T, Enokida H, Nakagawa M, Okamoto Y, et al: microRNA-504 inhibits cancer cell proliferation via targeting CDK6 in hypopharyngeal squamous cell carcinoma. Int J Oncol. 44:2085–2092. 2014.PubMed/NCBI

221 

Keklikoglou I, Koerner C, Schmidt C, Zhang JD, Heckmann D, Shavinskaya A, Allgayer H, Gückel B, Fehm T, Schneeweiss A, et al: MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways. Oncogene. 31:4150–4163. 2012. View Article : Google Scholar

222 

Song B, Ji W, Guo S, Liu A, Jing W, Shao C, Li G and Jin G: miR-545 inhibited pancreatic ductal adenocarcinoma growth by targeting RIG-I. FEBS Lett. 588:4375–4381. 2014. View Article : Google Scholar : PubMed/NCBI

223 

Bowen D, Zhe W, Xin Z, Shipeng F, Guoxin W, Jianxing H and Zhang B: MicroRNA-545 suppresses cell proliferation by targeting cyclin D1 and CDK4 in lung cancer cells. PLoS. 9:880222014. View Article : Google Scholar

224 

Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, et al: A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 353:1793–1801. 2005. View Article : Google Scholar : PubMed/NCBI

225 

Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI

226 

Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, et al: MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 65:7065–7070. 2005. View Article : Google Scholar : PubMed/NCBI

227 

Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, et al: MicroRNA signatures in human ovarian cancer. Cancer Res. 67:8699–8707. 2007. View Article : Google Scholar : PubMed/NCBI

228 

Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL and Visakorpi T: MicroRNA expression profiling in prostate cancer. Cancer Res. 67:6130–6135. 2007. View Article : Google Scholar : PubMed/NCBI

229 

Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 133:647–658. 2007. View Article : Google Scholar : PubMed/NCBI

230 

Zhu S, Si ML, Wu H and Mo YY: MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 282:14328–14336. 2007. View Article : Google Scholar : PubMed/NCBI

231 

Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A and Lund AH: Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 283:1026–1033. 2008. View Article : Google Scholar

232 

Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, Fabbri M, Coombes K, Alder H, Nakamura T, et al: MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood. 111:3183–3189. 2008. View Article : Google Scholar : PubMed/NCBI

233 

Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI

234 

White NM, Fatoohi E, Metias M, Jung K, Stephan C and Yousef GM: Metastamirs: A stepping stone towards improved cancer management. Nat Rev Clin Oncol. 8:75–84. 2011. View Article : Google Scholar

235 

Zhou L, Liu F, Wang X and Ouyang G: The roles of microRNAs in the regulation of tumor metastasis. Cell Biosci. 5:322015. View Article : Google Scholar : PubMed/NCBI

236 

Wang XH, Cai P, Wang MH and Wang Z: microRNA 25 promotes osteosarcoma cell proliferation by targeting the cell cycle inhibitor p27. Mol Med Rep. 10:855–859. 2014.PubMed/NCBI

237 

Siu MK, Tsai YC, Chang YS, Yin JJ, Suau F, Chen WY and Liu YN: Transforming growth factor-β promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway. Oncogene. 34:4767–4776. 2015. View Article : Google Scholar

238 

Xia X, Li Y, Wang W, Tang F, Tan J, Sun L, Li Q, Sun L, Tang B and He S: MicroRNA-1908 functions as a glioblastoma oncogene by suppressing PTEN tumor suppressor pathway. Mol Cancer. 14:1542015. View Article : Google Scholar : PubMed/NCBI

239 

Sachdeva M, Mito JK, Lee CL, Zhang M, Li Z, Dodd RD, Cason D, Luo L, Ma Y, Van Mater D, et al: MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest. 124:4305–4319. 2014. View Article : Google Scholar : PubMed/NCBI

240 

Tian Y, Luo A, Cai Y, Su Q, Ding F, Chen H and Liu Z: MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines. J Biol Chem. 285:7986–7994. 2010. View Article : Google Scholar : PubMed/NCBI

241 

Wang YY, Ye ZY, Zhao ZS, Li L, Wang YX, Tao HQ, Wang HJ and He XJ: Clinicopathologic significance of miR-10b expression in gastric carcinoma. Hum Pathol. 44:1278–1285. 2013. View Article : Google Scholar : PubMed/NCBI

242 

Chan JA, Krichevsky AM and Kosik KS: MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65:6029–6033. 2005. View Article : Google Scholar : PubMed/NCBI

243 

Liu W, Zabirnyk O, Wang H, Shiao YH, Nickerson ML, Khalil S, Anderson LM, Perantoni AO and Phang JM: miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer. Oncogene. 29:4914–4924. 2010. View Article : Google Scholar : PubMed/NCBI

244 

Fletcher CE, Dart DA, Sita-Lumsden A, Cheng H, Rennie PS and Bevan CL: Androgen-regulated processing of the oncomir miR-27a, which targets Prohibitin in prostate cancer. Hum Mol Genet. 21:3112–3127. 2012. View Article : Google Scholar : PubMed/NCBI

245 

Ng WL, Yan D, Zhang X, Mo YY and Wang Y: Over-expression of miR-100 is responsible for the low-expression of ATM in the human glioma cell line: M059J. DNA Repair (Amst). 9:1170–1175. 2010. View Article : Google Scholar

246 

Zheng YS, Zhang H, Zhang XJ, Feng DD, Luo XQ, Zeng CW, Lin KY, Zhou H, Qu LH, Zhang P, et al: MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia. Oncogene. 31:80–92. 2012. View Article : Google Scholar :

247 

Knackmuss U, Lindner SE, Aneichyk T, Kotkamp B, Knust Z, Villunger A and Herzog S: MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells. Cell Death Differ. 23:242–252. 2016. View Article : Google Scholar

248 

Park JK, Henry JC, Jiang J, Esau C, Gusev Y, Lerner MR, Postier RG, Brackett DJ and Schmittgen TD: miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor. Biochem Biophys Res Commun. 406:518–523. 2011. View Article : Google Scholar : PubMed/NCBI

249 

Kong W, He L, Coppola M, Guo J, Esposito NN, Coppola D and Cheng JQ: MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. J Biol Chem. 285:17869–17879. 2010. View Article : Google Scholar : PubMed/NCBI

250 

Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, Liu MF and Wang ED: MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 70:3119–3127. 2010. View Article : Google Scholar : PubMed/NCBI

251 

Czyzyk-Krzeska MF and Zhang X: MiR-155 at the heart of oncogenic pathways. Oncogene. 33:677–678. 2014. View Article : Google Scholar :

252 

Wang J and Wu J: Role of miR-155 in breast cancer. Front Biosci (Landmark Ed). 17:2350–2355. 2012. View Article : Google Scholar

253 

Ling N, Gu J, Lei Z, Li M, Zhao J, Zhang HT and Li X: microRNA-155 regulates cell proliferation and invasion by targeting FOXO3a in glioma. Oncol Rep. 30:2111–2118. 2013.PubMed/NCBI

254 

Musilova K and Mraz M: MicroRNAs in B-cell lymphomas: How a complex biology gets more complex. Leukemia. 29:1004–1017. 2015. View Article : Google Scholar

255 

Fontana L, Fiori ME, Albini S, Cifaldi L, Giovinazzi S, Forloni M, Boldrini R, Donfrancesco A, Federici V, Giacomini P, et al: AntagomiR-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS One. 3:e22362008. View Article : Google Scholar : PubMed/NCBI

256 

Segura MF, Hanniford D, Menendez S, Reavie L, Zou X, Alvarez-Diaz S, Zakrzewski J, Blochin E, Rose A, Bogunovic D, et al: Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci USA. 106:1814–1819. 2009. View Article : Google Scholar : PubMed/NCBI

257 

Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV, et al: MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 68:425–433. 2008. View Article : Google Scholar : PubMed/NCBI

258 

Zhang CZ, Zhang JX, Zhang AL, Shi ZD, Han L, Jia ZF, Yang WD, Wang GX, Jiang T, You YP, et al: MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma. Mol Cancer. 9:2292010. View Article : Google Scholar : PubMed/NCBI

259 

Garofalo M, Quintavalle C, Romano G, Croce CM and Condorelli G: miR221/222 in cancer: Their role in tumor progression and response to therapy. Curr Mol Med. 12:27–33. 2012. View Article : Google Scholar

260 

Quintavalle C, Garofalo M, Zanca C, Romano G, Iaboni M, del Basso De Caro M, Martinez-Montero JC, Incoronato M, Nuovo G, Croce CM, et al: miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTPμ. Oncogene. 31:858–868. 2012. View Article : Google Scholar

261 

Chen WX, Hu Q, Qiu MT, Zhong SL, Xu JJ, Tang JH and Zhao JH: miR-221/222: Promising biomarkers for breast cancer. Tumour Biol. 34:1361–1370. 2013. View Article : Google Scholar : PubMed/NCBI

262 

Matsuzaki J and Suzuki H: Role of MicroRNAs-221/222 in digestive systems. J Clin Med. 4:1566–1577. 2015. View Article : Google Scholar : PubMed/NCBI

263 

Würdinger T, Tannous BA, Saydam O, Skog J, Grau S, Soutschek J, Weissleder R, Breakefield XO and Krichevsky AM: miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell. 14:382–393. 2008. View Article : Google Scholar : PubMed/NCBI

264 

Shi W, Gerster K, Alajez NM, Tsang J, Waldron L, Pintilie M, Hui AB, Sykes J, P'ng C, Miller N, et al: MicroRNA-301 mediates proliferation and invasion in human breast cancer. Cancer Res. 71:2926–2937. 2011. View Article : Google Scholar : PubMed/NCBI

265 

Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, et al: A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Adv Exp Med Biol. 604:17–46. 2007. View Article : Google Scholar : PubMed/NCBI

266 

Xu Y, Jin J, Liu Y, Huang Z, Deng Y, You T, Zhou T, Si J and Zhuo W: Snail-regulated MiR-375 inhibits migration and invasion of gastric cancer cells by targeting JAK2. PLoS One. 9:e995162014. View Article : Google Scholar : PubMed/NCBI

267 

Lee DY, Deng Z, Wang CH and Yang BB: MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci USA. 104:20350–20355. 2007. View Article : Google Scholar : PubMed/NCBI

268 

Tu K, Liu Z, Yao B, Han S and Yang W: MicroRNA-519a promotes tumor growth by targeting PTEN/PI3K/AKT signaling in hepatocellular carcinoma. Int J Oncol. 48:965–974. 2016.

269 

Shao J, Cao J, Liu Y, Mei H, Zhang Y and Xu W: MicroRNA-519a promotes proliferation and inhibits apoptosis of hepatocellular carcinoma cells by targeting FOXF2. FEBS Open Bio. 5:893–899. 2015. View Article : Google Scholar : PubMed/NCBI

270 

Ward A, Shukla K, Balwierz A, Soons Z, König R, Sahin O and Wiemann S: MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer. J Pathol. 233:368–379. 2014. View Article : Google Scholar : PubMed/NCBI

271 

Tsang WP, Ng EK, Ng SS, Jin H, Yu J, Sung JJ and Kwok TT: Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis. 31:350–358. 2010. View Article : Google Scholar

272 

Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, Teruya-Feldstein J, Reinhardt F, Onder TT, Valastyan S, et al: miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol. 12:247–256. 2010.PubMed/NCBI

273 

Chen D, Sun Y, Wei Y, Zhang P, Rezaeian AH, Teruya-Feldstein J, Gupta S, Liang H, Lin HK, Hung MC, et al: LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat Med. 18:1511–1517. 2012. View Article : Google Scholar : PubMed/NCBI

274 

White RA, Neiman JM, Reddi A, Han G, Birlea S, Mitra D, Dionne L, Fernandez P, Murao K, Bian L, et al: Epithelial stem cell mutations that promote squamous cell carcinoma metastasis. J Clin Invest. 123:4390–4404. 2013. View Article : Google Scholar : PubMed/NCBI

275 

Ma L, Teruya-Feldstein J and Weinberg RA: Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 449:682–688. 2007. View Article : Google Scholar : PubMed/NCBI

276 

Lin J, Teo S, Lam DH, Jeyaseelan K and Wang S: MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme. Cell Death Dis. 3:e3982012. View Article : Google Scholar : PubMed/NCBI

277 

Zhang WL, Zhang JH, Wu XZ, Yan T and Lv W: miR-15b promotes epithelial-mesenchymal transition by inhibiting SMURF2 in pancreatic cancer. Int J Oncol. 47:1043–1053. 2015.PubMed/NCBI

278 

Wu Q, Yang Z, An Y, Hu H, Yin J, Zhang P, Nie Y, Wu K, Shi Y and Fan D: MiR-19a/b modulate the metastasis of gastric cancer cells by targeting the tumour suppressor MXD1. Cell Death Dis. 5:e11442014. View Article : Google Scholar : PubMed/NCBI

279 

Chang Y, Liu C, Yang J, Liu G, Feng F, Tang J, Hu L, Li L, Jiang F, Chen C, et al: MiR-20a triggers metastasis of gallbladder carcinoma. J Hepatol. 59:518–527. 2013. View Article : Google Scholar : PubMed/NCBI

280 

Zhao S, Yao D, Chen J, Ding N and Ren F: MiR-20a promotes cervical cancer proliferation and metastasis in vitro and in vivo. PLoS One. 10:e01209052015. View Article : Google Scholar : PubMed/NCBI

281 

Dean ZS, Riahi R and Wong PK: Spatiotemporal dynamics of microRNA during epithelial collective cell migration. Biomaterials. 37:156–163. 2015. View Article : Google Scholar :

282 

Peacock O, Lee AC, Cameron F, Tarbox R, Vafadar-Isfahani N, Tufarelli C and Lund JN: Inflammation and MiR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer. PLoS One. 9:e1102672014. View Article : Google Scholar : PubMed/NCBI

283 

Xu J, Zhang W, Lv Q and Zhu D: Overexpression of miR-21 promotes the proliferation and migration of cervical cancer cells via the inhibition of PTEN. Oncol Rep. 33:3108–3116. 2015.PubMed/NCBI

284 

Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S and Allgayer H: MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 27:2128–2136. 2008. View Article : Google Scholar

285 

Melnik BC: MiR-21: An environmental driver of malignant melanoma? J Transl Med. 13:2022015. View Article : Google Scholar : PubMed/NCBI

286 

Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O'Connor ST, Chin AR, et al: Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 25:501–515. 2014. View Article : Google Scholar : PubMed/NCBI

287 

Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, Chow A, O'Connor ST, Li S, Chin AR, et al: Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 17:183–194. 2015. View Article : Google Scholar : PubMed/NCBI

288 

Lin CW, Chang YL, Chang YC, Lin JC, Chen CC, Pan SH, Wu CT, Chen HY, Yang SC, Hong TM, et al: MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. Nat Commun. 4:18772013. View Article : Google Scholar : PubMed/NCBI

289 

Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D and Schiemann WP: TGF-β upregulates miR-181a expression to promote breast cancer metastasis. J Clin Invest. 123:150–163. 2013. View Article : Google Scholar

290 

Qiu Y, Luo X, Kan T, Zhang Y, Yu W, Wei Y, Shen N, Yi B and Jiang X: TGF-β upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1. Mol Biosyst. 10:679–685. 2014. View Article : Google Scholar : PubMed/NCBI

291 

Ren LH, Chen WX, Li S, He XY, Zhang ZM, Li M, Cao RS, Hao B, Zhang HJ, Qiu HQ, et al: MicroRNA-183 promotes proliferation and invasion in oesophageal squamous cell carcinoma by targeting programmed cell death 4. Br J Cancer. 111:2003–2013. 2014. View Article : Google Scholar : PubMed/NCBI

292 

Korpal M, Lee ES, Hu G and Kang Y: The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 283:14910–14914. 2008. View Article : Google Scholar : PubMed/NCBI

293 

Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celià-Terrassa T, Mercatali L, Khan Z, Goodarzi H, Hua Y, et al: Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 17:1101–1108. 2011. View Article : Google Scholar : PubMed/NCBI

294 

Park SM, Gaur AB, Lengyel E and Peter ME: The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22:894–907. 2008. View Article : Google Scholar : PubMed/NCBI

295 

Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y and Goodall GJ: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 10:593–601. 2008. View Article : Google Scholar : PubMed/NCBI

296 

Penna E, Orso F, Cimino D, Tenaglia E, Lembo A, Quaglino E, Poliseno L, Haimovic A, Osella-Abate S, De Pittà C, et al: microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C. EMBO J. 30:1990–2007. 2011. View Article : Google Scholar : PubMed/NCBI

297 

Penna E, Orso F, Cimino D, Vercellino I, Grassi E, Quaglino E, Turco E and Taverna D: miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation. Cancer Res. 73:4098–4111. 2013. View Article : Google Scholar : PubMed/NCBI

298 

Long H, Wang Z, Chen J, Xiang T, Li Q, Diao X and Zhu B: microRNA-214 promotes epithelial-mesenchymal transition and metastasis in lung adenocarcinoma by targeting the suppressor-of-fused protein (Sufu). Oncotarget. 6:38705–38718. 2015.PubMed/NCBI

299 

Liu X, Chen Q, Yan J, Wang Y, Zhu C, Chen C, Zhao X, Xu M, Sun Q, Deng R, et al: MiRNA-296-3p-ICAM-1 axis promotes metastasis of prostate cancer by possible enhancing survival of natural killer cell-resistant circulating tumour cells. Cell Death Dis. 4:e9282013. View Article : Google Scholar : PubMed/NCBI

300 

Vaira V, Faversani A, Martin NM, Garlick DS, Ferrero S, Nosotti M, Kissil JL, Bosari S and Altieri DC: Regulation of lung cancer metastasis by Klf4-Numb-like signaling. Cancer Res. 73:2695–2705. 2013. View Article : Google Scholar : PubMed/NCBI

301 

Ni F, Zhao H, Cui H, Wu Z, Chen L, Hu Z, Guo C, Liu Y, Chen Z, Wang X, et al: MicroRNA-362-5p promotes tumor growth and metastasis by targeting CYLD in hepatocellular carcinoma. Cancer Lett. 356:809–818. 2015. View Article : Google Scholar

302 

Chen D, Dang BL, Huang JZ, Chen M, Wu D, Xu ML, Li R and Yan GR: MiR-373 drives the epithelial-to-mesenchymal transition and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer. Oncotarget. 6:32701–32712. 2015.PubMed/NCBI

303 

Lu S, Zhu Q, Zhang Y, Song W, Wilson MJ and Liu P: Dual-functions of miR-373 and miR-520c by differently regulating the activities of MMP2 and MMP9. J Cell Physiol. 230:1862–1870. 2015. View Article : Google Scholar

304 

Glover AR, Zhao JT, Gill AJ, Weiss J, Mugridge N, Kim E, Feeney AL, Ip JC, Reid G, Clarke S, et al: MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma. Oncotarget. 6:36675–36688. 2015.PubMed/NCBI

305 

Babae N, Bourajjaj M, Liu Y, Van Beijnum JR, Cerisoli F, Scaria PV, Verheul M, Van Berkel MP, Pieters EH, Van Haastert RJ, et al: Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma. Oncotarget. 5:6687–6700. 2014. View Article : Google Scholar : PubMed/NCBI

306 

Wang W, Dai LX, Zhang S, Yang Y, Yan N, Fan P, Dai L, Tian HW, Cheng L, Zhang XM, et al: Regulation of epidermal growth factor receptor signaling by plasmid-based microRNA-7 inhibits human malignant gliomas growth and metastasis in vivo. Neoplasma. 60:274–283. 2013. View Article : Google Scholar : PubMed/NCBI

307 

Cortez MA, Valdecanas D, Zhang X, Zhan Y, Bhardwaj V, Calin GA, Komaki R, Giri DK, Quini CC, Wolfe T, et al: Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer. Mol Ther. 22:1494–1503. 2014. View Article : Google Scholar : PubMed/NCBI

308 

Wu X, Liu T, Fang O, Dong W, Zhang F, Leach L, Hu X and Luo Z: MicroRNA-708-5p acts as a therapeutic agent against metastatic lung cancer. Oncotarget. 7:2417–2432. 2016.

309 

Ge YF, Sun J, Jin CJ, Cao BQ, Jiang ZF and Shao JF: AntagomiR-27a targets FOXO3a in glioblastoma and suppresses U87 cell growth in vitro and in vivo. Asian Pac J Cancer Prev. 14:963–968. 2013. View Article : Google Scholar : PubMed/NCBI

310 

Shu M, Zheng X, Wu S, Lu H, Leng T, Zhu W, Zhou Y, Ou Y, Lin X, Lin Y, et al: Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells. Mol Cancer. 10:592011. View Article : Google Scholar : PubMed/NCBI

311 

Rather MI, Nagashri MN, Swamy SS, Gopinath KS and Kumar A: Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: Implications for cancer therapeutics. J Biol Chem. 288:608–618. 2013. View Article : Google Scholar :

312 

Haug BH, Henriksen JR, Buechner J, Geerts D, Tømte E, Kogner P, Martinsson T, Flægstad T, Sveinbjørnsson B and Einvik C: MYCN-regulated miRNA-92 inhibits secretion of the tumor suppressor DICKKOPF-3 (DKK3) in neuroblastoma. Carcinogenesis. 32:1005–1012. 2011. View Article : Google Scholar : PubMed/NCBI

313 

Tang H, Liu X, Wang Z, She X, Zeng X, Deng M, Liao Q, Guo X, Wang R, Li X, et al: Interaction of hsa-miR-381 and glioma suppressor LRRC4 is involved in glioma growth. Brain Res. 1390:21–32. 2011. View Article : Google Scholar : PubMed/NCBI

314 

Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson EG, Teruya-Feldstein J, Bell GW and Weinberg RA: Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol. 28:341–347. 2010. View Article : Google Scholar : PubMed/NCBI

315 

Mercatelli N, Coppola V, Bonci D, Miele F, Costantini A, Guadagnoli M, Bonanno E, Muto G, Frajese GV, De Maria R, et al: The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice. PLoS One. 3:e40292008. View Article : Google Scholar : PubMed/NCBI

316 

Zhao Y, Zhao L, Ischenko I, Bao Q, Schwarz B, Nieß H, Wang Y, Renner A, Mysliwietz J, Jauch KW, et al: Antisense inhibition of microRNA-21 and microRNA-221 in tumor-initiating stem-like cells modulates tumorigenesis, metastasis, and chemotherapy resistance in pancreatic cancer. Target Oncol. 10:535–548. 2015. View Article : Google Scholar : PubMed/NCBI

317 

Wagenaar TR, Zabludoff S, Ahn SM, Allerson C, Arlt H, Baffa R, Cao H, Davis S, Garcia-Echeverria C, Gaur R, et al: Anti-miR-21 suppresses hepatocellular carcinoma growth via broad transcriptional network deregulation. Mol Cancer Res. 13:1009–1021. 2015. View Article : Google Scholar : PubMed/NCBI

318 

Fabani MM, Abreu-Goodger C, Williams D, Lyons PA, Torres AG, Smith KG, Enright AJ, Gait MJ and Vigorito E: Efficient inhibition of miR-155 function in vivo by peptide nucleic acids. Nucleic Acids Res. 38:4466–4475. 2010. View Article : Google Scholar : PubMed/NCBI

319 

Brognara E, Fabbri E, Aimi F, Manicardi A, Bianchi N, Finotti A, Breveglieri G, Borgatti M, Corradini R, Marchelli R, et al: Peptide nucleic acids targeting miR-221 modulate p27Kip1 expression in breast cancer MDA-MB-231 cells. Int J Oncol. 41:2119–2127. 2012.PubMed/NCBI

320 

Yan LX, Wu QN, Zhang Y, Li YY, Liao DZ, Hou JH, Fu J, Zeng MS, Yun JP, Wu QL, et al: Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth. Breast Cancer Res. 13:R22011. View Article : Google Scholar : PubMed/NCBI

321 

Zhang J and Ma L: MicroRNA control of epithelial-mesenchymal transition and metastasis. Cancer Metastasis Rev. 31:653–662. 2012. View Article : Google Scholar : PubMed/NCBI

322 

Zaravinos A, Radojicic J, Lambrou GI, Volanis D, Delakas D, Stathopoulos EN and Spandidos DA: Expression of miRNAs involved in angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and activation of metastasis in bladder cancer. J Urol. 188:615–623. 2012. View Article : Google Scholar : PubMed/NCBI

323 

Kiesslich T, Pichler M and Neureiter D: Epigenetic control of epithelial-mesenchymal-transition in human cancer. Mol Clin Oncol. 1:3–11. 2013.PubMed/NCBI

324 

Lei C, Wang Y, Huang Y, Yu H, Huang Y, Wu L and Huang L: Up-regulated miR155 reverses the epithelial-mesenchymal transition induced by EGF and increases chemo-sensitivity to cisplatin in human Caski cervical cancer cells. PLoS One. 7:e523102012. View Article : Google Scholar

325 

Koutsaki M, Spandidos DA and Zaravinos A: Epithelial-mesenchymal transition-associated miRNAs in ovarian carcinoma, with highlight on the miR-200 family: Prognostic value and prospective role in ovarian cancer therapeutics. Cancer Lett. 351:173–181. 2014. View Article : Google Scholar : PubMed/NCBI

326 

Gao H, Teng C, Huang W, Peng J and Wang C: SOX2 promotes the epithelial to mesenchymal transition of esophageal squamous cells by modulating Slug expression through the activation of STAT3/HIF-α signaling.

327 

Lambertini E, Lolli A, Vezzali F, Penolazzi L, Gambari R and Piva R: Correlation between Slug transcription factor and miR-221 in MDA-MB-231 breast cancer cells. BMC Cancer. 12:4452012. View Article : Google Scholar : PubMed/NCBI

328 

Qiu G, Lin Y, Zhang H and Wu D: miR-139-5p inhibits epithelial-mesenchymal transition, migration and invasion of hepatocellular carcinoma cells by targeting ZEB1 and ZEB2. Biochem Biophys Res Commun. 463:315–321. 2015. View Article : Google Scholar : PubMed/NCBI

329 

Bezzerri V, Borgatti M, Finotti A, Tamanini A, Gambari R and Cabrini G: Mapping the transcriptional machinery of the IL-8 gene in human bronchial epithelial cells. J Immunol. 187:6069–6081. 2011. View Article : Google Scholar : PubMed/NCBI

330 

Raychaudhuri B and Vogelbaum MA: IL-8 is a mediator of NF-κB induced invasion by gliomas. J Neurooncol. 101:227–235. 2011. View Article : Google Scholar

331 

Xie TX, Xia Z, Zhang N, Gong W and Huang S: Constitutive NF-κB activity regulates the expression of VEGF and IL-8 and tumor angiogenesis of human glioblastoma. Oncol Rep. 23:725–732. 2010.PubMed/NCBI

332 

Sun S, Wang Q, Giang A, Cheng C, Soo C, Wang CY, Liau LM and Chiu R: Knockdown of CypA inhibits interleukin-8 (IL-8) and IL-8-mediated proliferation and tumor growth of glioblastoma cells through down-regulated NF-κB. J Neurooncol. 101:1–14. 2011. View Article : Google Scholar

333 

Gabellini C, Castellini L, Trisciuoglio D, Kracht M, Zupi G and Del Bufalo D: Involvement of nuclear factor-kappa B in bcl-xL-induced interleukin 8 expression in glioblastoma. J Neurochem. 107:871–882. 2008. View Article : Google Scholar : PubMed/NCBI

334 

Yang TQ, Lu XJ, Wu TF, Ding DD, Zhao ZH, Chen GL, Xie XS, Li B, Wei YX, Guo LC, et al: MicroRNA-16 inhibits glioma cell growth and invasion through suppression of BCL2 and the nuclear factor-κB1/MMP9 signaling pathway. Cancer Sci. 105:265–271. 2014. View Article : Google Scholar : PubMed/NCBI

335 

Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, Yee AJ, Ang LC, He C, Shan SW, et al: MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-β8. Oncogene. 30:806–821. 2011. View Article : Google Scholar

336 

Magge SN, Malik SZ, Royo NC, Chen HI, Yu L, Snyder EY, O'Rourke DM and Watson DJ: Role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in migration of neural progenitor cells toward glial tumors. J Neurosci Res. 87:1547–1555. 2009. View Article : Google Scholar : PubMed/NCBI

337 

Nazarenko I, Hede SM, He X, Hedrén A, Thompson J, Lindström MS and Nistér M: PDGF and PDGF receptors in glioma. Ups J Med Sci. 117:99–112. 2012. View Article : Google Scholar : PubMed/NCBI

338 

Cai JJ, Qi ZX, Chen LC, Yao Y, Gong Y and Mao Y: miR-124 suppresses the migration and invasion of glioma cells in vitro via Capn4. Oncol Rep. 35:284–290. 2015.PubMed/NCBI

339 

Cheng Y, Li Y, Nian Y, Liu D, Dai F and Zhang J: STAT3 is involved in miR-124-mediated suppressive effects on esophageal cancer cells. BMC Cancer. 15:3062015. View Article : Google Scholar : PubMed/NCBI

340 

Dong LL, Chen LM, Wang WM and Zhang LM: Decreased expression of microRNA-124 is an independent unfavorable prognostic factor for patients with breast cancer. Diagn Pathol. 10:452015. View Article : Google Scholar : PubMed/NCBI

341 

Long QZ, Du YF, Liu XG, Li X and He DL: miR-124 represses FZD5 to attenuate P-glycoprotein-mediated chemo-resistance in renal cell carcinoma. Tumour Biol. 36:7017–7026. 2015. View Article : Google Scholar : PubMed/NCBI

342 

Lu SH, Jiang XJ, Xiao GL, Liu DY and Yuan XR: miR-124a restoration inhibits glioma cell proliferation and invasion by suppressing IQGAP1 and β-catenin. Oncol Rep. 32:2104–2110. 2014.PubMed/NCBI

343 

Chen SM, Chou WC, Hu LY, Hsiung CN, Chu HW, Huang YL, Hsu HM, Yu JC and Shen CY: The Effect of MicroRNA-124 overexpression on anti-tumor drug sensitivity. PLoS One. 10:e01284722015. View Article : Google Scholar : PubMed/NCBI

344 

Fabbri E, Brognara E, Montagner G, Ghimenton C, Eccher A, Cantù C, Khalil S, Bezzerri V, Provezza L, Bianchi N, et al: Regulation of IL-8 gene expression in gliomas by microRNA miR-93. BMC Cancer. 15:6612015. View Article : Google Scholar : PubMed/NCBI

345 

Fabbri E, Montagner G, Bianchi N, Finotti A, Borgatti M, Lampronti I, Cabrini G and Gambari R: MicroRNA miR-93-5p regulates expression of IL-8 and VEGF in neuroblastoma SK-N-AS cells. Oncol Rep. 35:2866–2872. 2016.PubMed/NCBI

346 

Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafrè SA and Farace MG: miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem. 282:23716–23724. 2007. View Article : Google Scholar : PubMed/NCBI

347 

Lu X, Zhao P, Zhang C, Fu Z, Chen Y, Lu A, Liu N, You Y, Pu P and Kang C: Analysis of miR-221 and p27 expression in human gliomas. Mol Med Rep. 2:651–656. 2009.PubMed/NCBI

348 

Gillies JK and Lorimer IA: Regulation of p27Kip1 by miRNA 221/222 in glioblastoma. Cell Cycle. 6:2005–2009. 2007. View Article : Google Scholar : PubMed/NCBI

349 

Wang Y, Wang X, Zhang J, Sun G, Luo H, Kang C, Pu P, Jiang T, Liu N and You Y: MicroRNAs involved in the EGFR/PTEN/AKT pathway in gliomas. J Neurooncol. 106:217–224. 2012. View Article : Google Scholar

350 

Ueda R, Kohanbash G, Sasaki K, Fujita M, Zhu X, Kastenhuber ER, McDonald HA, Potter DM, Hamilton RL, Lotze MT, et al: Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1. Proc Natl Acad Sci USA. 106:10746–10751. 2009. View Article : Google Scholar : PubMed/NCBI

351 

Zhang J, Han L, Ge Y, Zhou X, Zhang A, Zhang C, Zhong Y, You Y, Pu P and Kang C: miR-221/222 promote malignant progression of glioma through activation of the Akt pathway. Int J Oncol. 36:913–920. 2010.PubMed/NCBI

352 

Zhang C, Jiang T, Wang J, Cheng J, Pu P and Kang C: MiR-221/222 promote the growth of malignant glioma cells by regulating its target genes, molecular targets of CNS tumors. Dr Garami Miklos : ISBN: 978-953-307-736-9InTech; pp. 461–482. 2011

353 

Sarkar S, Dubaybo H, Ali S, Goncalves P, Kollepara SL, Sethi S, Philip PA and Li Y: Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA. Am J Cancer Res. 3:465–477. 2013.PubMed/NCBI

354 

Zhang C, Kang C, You Y, Pu P, Yang W, Zhao P, Wang G, Zhang A, Jia Z, Han L, et al: Co-suppression of miR-221/222 cluster suppresses human glioma cell growth by targeting p27Kip1 in vitro and in vivo. Int J Oncol. 34:1653–1660. 2009. View Article : Google Scholar : PubMed/NCBI

355 

Zhang R, Pang B, Xin T, Guo H, Xing Y, Xu S, Feng B, Liu B and Pang Q: Plasma miR-221/222 family as novel descriptive and prognostic biomarkers for glioma. Mol Neurobiol. 53:1452–1460. 2016. View Article : Google Scholar

356 

Yang Y, Li F, Saha MN, Abdi J, Qiu L and Chang H: miR-137/197 induce apoptosis and suppress tumorigenicity by targeting MCL-1 in multiple myeloma. Clin Cancer Res. 21:2399–2411. 2015. View Article : Google Scholar : PubMed/NCBI

357 

Lee SH, Jung YD, Choi YS and Lee YM: Targeting of RUNX3 by miR-130a and miR-495 cooperatively increases cell proliferation and tumor angiogenesis in gastric cancer cells. Oncotarget. 6:33269–33278. 2015.PubMed/NCBI

358 

Brognara E, Fabbri E, Montagner G, Gasparello J, Manicardi A, Corradini R, Bianchi N, Finotti A, Breveglieri G, Borgatti M, et al: High levels of apoptosis are induced in human glioma cell lines by co-administration of peptide nucleic acids targeting miR-221 and miR-222. Int J Oncol. 48:1029–1038. 2016.

359 

Giunti L, da Ros M, Vinci S, Gelmini S, Iorio AL, Buccoliero AM, Cardellicchio S, Castiglione F, Genitori L, de Martino M, et al: Anti-miR21 oligonucleotide enhances chemosensitivity of T98G cell line to doxorubicin by inducing apoptosis. Am J Cancer Res. 5:231–242. 2014.

360 

Gao C, Peng FH and Peng LK: MiR-200c sensitizes clear-cell renal cell carcinoma cells to sorafenib and imatinib by targeting heme oxygenase-1. Neoplasma. 61:680–689. 2014. View Article : Google Scholar : PubMed/NCBI

361 

Pogribny IP, Filkowski JN, Tryndyak VP, Golubov A, Shpyleva SI and Kovalchuk O: Alterations of microRNAs and their targets are associated with acquired resistance of MCF-7 breast cancer cells to cisplatin. Int J Cancer. 127:1785–1794. 2010. View Article : Google Scholar : PubMed/NCBI

362 

Suto T, Yokobori T, Yajima R, Morita H, Fujii T, Yamaguchi S, Altan B, Tsutsumi S, Asao T and Kuwano H: MicroRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation. Carcinogenesis. 36:338–345. 2015. View Article : Google Scholar

363 

Liu R, Liu X, Zheng Y, Gu J, Xiong S, Jiang P, Jiang X, Huang E, Yang Y, Ge D, et al: MicroRNA-7 sensitizes non-small cell lung cancer cells to paclitaxel. Oncol Lett. 8:2193–2200. 2014.PubMed/NCBI

364 

Gomes SE, Simões AE, Pereira DM, Castro RE, Rodrigues CM and Borralho PM: miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells. Oncotarget. Jan 25–2016.(Epub ahead of print).

365 

Costa PM, Cardoso AL, Nóbrega C, Pereira de Almeida LF, Bruce JN, Canoll P and Pedroso de Lima MC: MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma. Hum Mol Genet. 22:904–918. 2013. View Article : Google Scholar :

366 

Qian X, Ren Y, Shi Z, Long L, Pu P, Sheng J, Yuan X and Kang C: Sequence-dependent synergistic inhibition of human glioma cell lines by combined temozolomide and miR-21 inhibitor gene therapy. Mol Pharm. 9:2636–2645. 2012. View Article : Google Scholar : PubMed/NCBI

367 

Zhang S, Han L, Wei J, Shi Z, Pu P, Zhang J, Yuan X and Kang C: Combination treatment with doxorubicin and microRNA-21 inhibitor synergistically augments anticancer activity through upregulation of tumor suppressing genes. Int J Oncol. 46:1589–1600. 2015.PubMed/NCBI

368 

Zhang Q, Ran R, Zhang L, Liu Y, Mei L, Zhang Z, Gao H and He Q: Simultaneous delivery of therapeutic antagomirs with paclitaxel for the management of metastatic tumors by a pH-responsive anti-microbial peptide-mediated liposomal delivery system. J Control Release. 197:208–218. 2015. View Article : Google Scholar

369 

Fan L, Yang Q, Tan J, Qiao Y, Wang Q, He J, Wu H and Zhang Y: Dual loading miR-218 mimics and Temozolomide using AuCOOH@FA-CS drug delivery system: Promising targeted anti-tumor drug delivery system with sequential release functions. J Exp Clin Cancer Res. 34:1062015. View Article : Google Scholar

370 

Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A, Cai W, Chirino LM, Yang GR, Bronson R, et al: Small RNA combination therapy for lung cancer. Proc Natl Acad Sci USA. 111:E3553–E3561. 2014. View Article : Google Scholar : PubMed/NCBI

371 

Nishimura M, Jung EJ, Shah MY, Lu C, Spizzo R, Shimizu M, Han HD, Ivan C, Rossi S, Zhang X, et al: Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment. Cancer Discov. 3:1302–1315. 2013. View Article : Google Scholar : PubMed/NCBI

372 

Hu X, Li W, Liu G, Wu H, Gao Y, Chen S, He D and Zhang Y: The effect of Bcl-2 siRNA combined with miR-15a oligonucleotides on the growth of Raji cells. Med Oncol. 30:4302013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July-2016
Volume 49 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Gambari R, Brognara E, Spandidos DA and Fabbri E: Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review). Int J Oncol 49: 5-32, 2016.
APA
Gambari, R., Brognara, E., Spandidos, D.A., & Fabbri, E. (2016). Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review). International Journal of Oncology, 49, 5-32. https://doi.org/10.3892/ijo.2016.3503
MLA
Gambari, R., Brognara, E., Spandidos, D. A., Fabbri, E."Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review)". International Journal of Oncology 49.1 (2016): 5-32.
Chicago
Gambari, R., Brognara, E., Spandidos, D. A., Fabbri, E."Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review)". International Journal of Oncology 49, no. 1 (2016): 5-32. https://doi.org/10.3892/ijo.2016.3503