Copyright ©The Author(s) 2015.
World J Biol Chem. Aug 26, 2015; 6(3): 162-208
Published online Aug 26, 2015. doi: 10.4331/wjbc.v6.i3.162
Table 4 Targets and pathways influenced by the downregulated myomiRs in different cancers
Downregulated miR-1
miR-1 downregulation influences multiple cancer-related pathway processes, and promotes cell proliferation and motilityEpigenetic promoter hypermethylation reduces miR-1/-133a expression in (a subset of) human prostate tumorsReduced miR-1, miR-133a (and miR-206)Human prostate tumors[102]
Actin filament network-associated genes: FN1, LASP1, XPO6, CLCN3 and G6PD; Cell cycle and DNA damage control genes: BRCA1, CHK1, MCM7; Histone acetylation: HDAC4; Oncogenes: NOTCH3 and PTMAmiR-1 downregulation associated with upregulation of multiple cancer-related pathway processesReduced miR-1;Human prostate cell lines, LNCaP, 22Rv1, PC-3 and RWPE-1[102]
Exogenous introduction of miR-1 or miR-206 caused similar inhibition of various cancer-related pathway genes
HSPB1HSPB1 restores oncogenic pathways in prostate cancer cellsDownregulates miR-1 expressionProgressive prostate cancer PCa cells[252]
XPO6 and TWF1 (PTK9)Inverse expression between miR-1, XPO6 and TWF1 proteins in prostate cancer cell linesDownregulated miR-1 expressionProstate cancer cell cultures[253]
CCND2, CXCR4, and SDF-1αInverse expression between miR-1 and CXCR4 and SDF-1α protein levels in thyroid carcinomasStrongly downregulated miR-1 expression in thyroid adenomas and carcinomasThyroid adenomas and carcinomas[254]
METMET upregulatedReduced miR-1Colon cancer[101]
Reduced miR-1, -133bColon cancer[87]
MET, Pim-1 (Ser/Thr kinase), FoxP1 and HDAC4miR-1 downregulated,MET, Pim-1, FoxP1 and HDAC4 are often upregulated in lung cancerNSCLC tissue and A549 cell line[100]
miR-1 targets MET, Pim-1, and may regulate FoxP1 and HDAC4
Fibronectin1Fibronectin1 upregulatedmiR-1 downregulatedLaryngeal SCC Hep2 cells[255]
Met, Twf1 and Ets1 and Bag4Met, Twf1 and Ets1 and Bag4 activities upregulatedmiR-1 downregulatedMouse cutaneous squamous cell carcinomas[256]
Mediator complex subunit 1 (Med1) and 31 (Med31)Med1 and Med31 activation result in increased Met activityReduced miR-1; miR-1 targets Med 1 and Med 31Osteosarcoma[257]
NOTCH3 upregulates Asef expression, activating the Asef promoter, enhancing cell migrationNOTCH3 upregulatedReduced miR-1; miR-1 targets NOTCH3Colorectal tumor cells[258]
Overexpression of PIK3CA correlates with low miR-1 expression in NSCLC tissues71% of NSCLC samples had high PIK3CA expression69% of NSCLC samples had low miR-1 expressionPredictors of lymph node metastasis in NSCLC tissues[259]
SLUG expression downregulated by miR-1Transcriptional repressor of E-cadherin, or an inducer of epithelial-to-mesenchymal transitionOverexpression of miR-1 induces morphological change from a mesenchymal to an epithelial characterNSCLC A549 cell line[260]
SLUG expression high in chordoma tissuemiR-1 inhibited cell proliferation both time- and dose-dependently in chordomaTransfection of MiR-1 inhibited Slug expressionmR-1 transfected chordoma cells[261]
Slug overexpressed in advanced chordoma tissues and chordoma cells
MET expression high in chordoma tissuemiR-1 downregulated 97% of chordoma samplesMiR-1 directly targets METDecreasing miR-1 expression levels correlated with severity of clinical prognosis[262]
SRSF9/SRp30cExogenous upregulation of miR-1 expressionNovel apoptosis pathway involving SRSF9/SRp30c mediates tumor suppressionBladder cancer (TCC) cells[263]
ANXA2 is essential for glioblastoma growth and invasionANXA2 is highly abundant protein in glioblastoma-derived extracellular vesiclesmiR-1 directly targets ANXA2;Human Glioblastoma cells; miR-1 orchestrates glioblastoma extracellular vesicle function[264]
Reduced miR-1 in glioblastoma
EDN1miR-1 downregulated in gastric cancermiR-1 causes ET-1 silencing in gastric cancer cell linesGastric cancer tissue compared with adjacent normal tissue[265]
EDN1Elevated expression of EDN1 and reduced miR-1 levelmiR-1 directly targets EDN1Human liver cancer tissues[266, 267]
Overexpressed EDN1Enhanced in vitro cell proliferation and cell migration. Upregulation of several cell cycle/proliferation- and migration-specific genesUpregulated UPR pathway mediators, spliced XBP1, ATF6, IRE1, and PERK at both RNA and protein levels293T cells[267]
AKT inhibitor diminished the unfolded protein response and eliminated EDN1-induced cell migrationEDN1 effects act via activation of the AKT pathwayResults to enhance the UPR and subsequently activate the expression of downstream genes293T cells[267]
Edn1Induced steatosis, fibrosis, glycogen accumulation, bile duct dilation, hyperplasia, and HCCLiver-specific edn1 expressionTransgenic Zebrafish liver[267]
API5API5 expression upregulated thus inhibiting apoptosismiR-1 expression downregulatedHuman liver cancer tissues[268]
Apoptosis activated, API5 reducedOverexpression of miR-1HepG2 liver cancer cells
Phosphorylation of ERK and AKT; LASP1Overexpression of miR-1 inhibits phosphorylation of ERK and AKT and reverses EMT process via inhibition of MAPK and PI3K/AKT pathwaysMAPK and PI3K/AKT pathwaysTransgenic miR-1 expressing CRC cell lines[269]
LASP1 expression upregulatedUpregulated LASP1 stimulates EMT resulting in cell proliferation and migrationmiR-1 downregulatedColorectal tumor tissue[269]
PIK3CAIncreased expression of PIK3CADownregulated miR-1 expression in lung cancerNSCLC tissue with poor patient prognosis[259]
PIK3CA indirectly regulating pAKT and survivin proteinsOverexpressed miR-1 downregulated PIK3CA causing reduced pAKT and survivin proteinsExogenously overexpressed miR-1 targets PIK3CA directly.NSCLC A549 cell line[270]
Signalling pathways such as TGF-β, ErbB3, WNT and VEGFA, and cell motility or adhesionEctopic expression of miR-1 and miR-145 downregulates VEGFA and AXL, respectivelyHighly downregulated expression of miR-1, miR-133, miR-143 and miR-145 in gall bladder cancerGall bladder tumor samples and GBC NOZ cell line[271]
lncRNA UCA1Lnc RNA UCA1 upregulated in bladder cancer (TCC);Downregulated miR-1 expression in bladder cancer (TCC); miR-1 targets lnc RNA UCA1 for downregulationHuman bladder cancer (TCC) tissue[156]
Inverse relationship between miR-1 and lnc UCA1
Downregulated miR-133a
MoesinMoesin upregulatedReduced miR-133aHNSCC[143]
ARPC5ARPC5 upregulatedReduced miR-133aHNSCC[272]
ARPC5 and GSTP1ARPC5 and GSTP1 upregulatedReduced miR-133a (and miR-206)Lung carcinoma[115]
IGF-1R, TGFBR1, and EGFR are downregulatedRestoration of ectopic-expression of miR-133a in NSCLC suppresses metastatic capacitymiR-133a inhibits cell invasiveness and cell growth via suppression of IGF-1R, TGFBR1 and EGFRNSCLCs[131]
Low expression of miR-133a is characteristic of pancreas tissueReduced miR-133aPDAC[103]
CDC42CDC42 upregulated causing downstream activation of PAKsmiR-133 downregulatedGastric cancer tissues[273]
GSTP1Upregulated GSTP1Downregulation of miR-133a in cancerBladder cancer (TCC) cell lines[144]
Enforced downregulation of GSTP1 inhibits cell proliferation and growth;Enforced upregulation of miR-133a and miR-133b induces cell apoptosis
GSTP1 in cancer specimensGSTP1 upregulatedReduced miR-133aBladder cancer (TCC) tissue[144]
Actin-binding protein, FSCN1Upregulated FSCN1;Downregulation of miR-133a;Bladder cancer (TCC) tissue[274]
Enforced downregulation of FSCN1 inhibits cell proliferation, migration and invasionForced UP exp of miR-133a inhibits cell proliferation, migration and invasion
EGFR/AKT signalling pathwayUpregulated EGFR;Downregulated miR-133a;Human MCF-7 and MDA-MB-231 breast cancer cell lines[275]
Activated pAkt-1Enforced expression of miR-133a inhibits EGRF translation; causes inhibition of Akt protein phosphorylation and its nuclear translocation
Bcl-xL and Mcl-1 expressionUpregulated Bcl-xL and Mcl-1Downregulated miR-133a correlated with tumor progression and poor patient prognosis;Primary human osteosarcoma tissues;[276]
Osteosarcoma cell lines
E3 ubiquitin protein ligaseDownregulation of p21 and p53 proteinsDownregulated miR-133aPrimary CRC tissues[277]
Enhanced sensitivity to doxorubicin and oxaliplatinEnhancing apoptosis and inhibited cell proliferationEctopic upregulation of miR-133aCRC cell lines[277]
LASP1 upregulatedmiR-133a expression downregulatedmiR-133a targets LASP1CRC tissues and cell lines[278]
FTL protein upregulatedmiR-133a expression downregulatedmiR-133a targets downregulation of FTL proteinPatient breast cancer tissue[279]
Increased sensitivity to chemotherapeutic drugs doxorubicin and cisplatinExogenous upregulation of miR-133a expressionDownregulation of FTL proteinHuman MCF-7 breast cancer cells[279]
Poor survival during breast cancer; upregulated FSCN1Loss of miR-133a expressionFSCN1 is a direct target gene of miR-133aBreast cancer tissue[280]
FSCN1 downregulatedRestoration of miR-133a expressionInhibited breast cancer cell growth and invasionBreast cancer cell line[280]
lncRNA Malat1/Srf/miR-133 regulatory loopMalat1 transcript has a functional miR-133 target site, miR-133 acts as a competing endogenous RNA, regulating Malat1 levelsIn vitro depletion of Malat1 in C2C12 cells reduces Srf activity, Srf is an enhancer of miR-133 expression; feed-back regulation loop involving miR-133Mouse myoblast C2C12 cells[164]
lncRNA MALAT1MALAT1 is overexpressed in 46% of ESCC tissues, primarily in high-stage tumors, high expression correlates with lymph node metastasisIn vitro depletion of MALAT1 suppresses tumor cell proliferation, cell migration and invasion; G2/M phase arrest was induced and the ratio of apoptotic cells increasedHuman ESCC[162]
WIF1/lncRNA MALAT1WIF1 (strong tumor suppressor) is systematically downregulated in glioblastomaWIF1 down regulation correlates with strong upregulation of MALAT1. In vitro depletion of MALAT1 suppresses tumor cell proliferationGlioblastoma[163]
Downregulated miR-133b
Fascin-1 mRNAFSCN1 upregulatedReduced miR-133bHigh-grade GIST tissue[281]
BCL-2 family (MCL-1 and BCL2L2)MCL-1 and BCL2L2 upregulatedReduced miR-133bLung cancer[85]
FAIM antiapoptotic protein and GSTP1miR-133b directly targets FAIM and GSTP1Downregulated miR-133bmiR-133b expression significantly downregulated in 75% of prostate cancer tumor specimens[282]
Gli1Gli1 upregulatedGli1 inversely correlated with downregulated expression of miR-133bGastric cancer[283]
Bcl-w and Akt1Bcl-w and Akt1 proteins overexpressed significantlymiR-133b significantly downregulatedBladder cancer tissues[284]
miR-133b downregulated in tumors compared to surrounding tissueGastric and esophageal adenocarcinomas[285]
Endometrial sarcoma, leiomyosarcoma, and mixed epithelial-mesenchymal tumors[286]
Downregulated miR-206
Notch3/ miR-206Downregulated Notch3, blocking of the anti-apoptotic activity of Notch3Forced expression of miR-206 strongly induced apoptotic cell death via; also inhibited cell migration and focus formationHeLa cells[287]
MetUpregulated MetmiR-206 downregulatedHuman rhabdomyosarcoma[288]
HGFRUpregulated HGFRmiR-206 downregulatedHuman breast cancer cells[289]
KLF4Upregulated KLF4miR-206 downregulatedRK3E breast epithelium cells[108]
KLF4; RAS-ERK signallingUpregulated KLF4 promotes RAS-ERK signallingmiR-206 downregulatedTNBC cells[290]
Endogenous KLF4 binds the promoter regions stimulates expression of miR-206
RASA1 and SPRED1miR-206 inhibits translation of the RAS pathway suppressors RASA1 and SPRED1Suppression of RASA1 or SPRED1 increased levels of GTP-bound, wild-type RAS and activated ERK 1/2
VEGFVEGF upregulated in Laryngeal SCC tissuesMiR-206 strongly downregulated in LSCC tissuesLaryngeal SCC cancer tissue and cells[113]
VEGFVEGF upregulated in ccRCC tissuesMiR-206 strongly downregulated in ccRCC tissuesccRCC tissues assayed by Deep Sequencing[291]
Cdc42, MMP-2 and MMP-9Upregulated Cdc42, MMP-2 and MMP-9miR-206 downregulatedHuman breast cancer tissues[292]
ERαmiR-206 directly targets ERα 3'-untranslated regionMiR-206 inhibited by ERα agonists, indicating a mutually (double) inhibitory feedback loop;Estrogen stimulated breast cancer cell lines[293]
miR-206 downregulated[109]
Upregulated ERαMCF-7 breast cancer cells[294]
ERαUpregulated ERαmiR-206 downregulatedEEC tissue[110]
K-RasK-Ras is direct target of miR-206;Low miR-206 potentiates metastases, and shorter overall survivalOSCC tissue samples and cell lines[295]
MiR-206 expression significantly downregulated and k-Ras upregulated on OSCC tissues
MiR-206Enforced upregulated of miR-206 attenuated cell proliferation, increased apoptosis and inhibited cell migration and invasionMiR-206 strongly downregulated in lung cancer tissuesLung cancer - tissues and cell lines[107]
EGFR/MAPK signalling switches MCF-7 breast cancer cells from ERα-positive, Luminal-A phenotype to ERα-negative, basal-like phenotypeEGFR signalling represses estrogenic responses in MCF-7 cells by enhancing miR-206 activitymiR-206 downregulates steroid receptor co-activators SRC-1 and SRC-3 and GATA-3 transcription factor, directlyMCF-7 breast cancer cells[296]
Elevated miR-206 reduces cell proliferation, enhances apoptosis, and reduces numerous estrogen-responsive genes
Greater lymph node metastasis, venous invasion, and at a more advanced stagemiR-206 expression strongly downregulatedCorrelates with tumor progressionHuman gastric cancer tissue[297]
CCND2miR-206 expression strongly downregulatedCorrelates with upregulation of CCND2 and cancer progressionHuman breast cancer[298]
Human gastric cancer[299]
METmiR-206 expression strongly downregulatedUpregulation of METPapillary thyroid carcinoma[300]
Prognostic signature of metastatic colorectal cancermiR-206 expression strongly downregulatedPrognostic signature of metastases: miRs 21, 135a, 335, 206 and let-7aMetastatic CRC[301]
Notch3, Hes1, Bcl-2 and MMP-9;Exogenous upregulation of miR-206 expression;Notch3, Hes1, Bcl-2 and MMP-9 downregulated at both mRNA and protein level;Human HHC Hep2 cells.[302]
p57, Bax and caspase-3miR-206 is a potent tumor supressorp57 and Bax upregulated, and cleaved caspase-3 protein upregulatedReduced apoptosis, and cell migration in HepG2 cells overexpressing miR-206
STC2, HDAC4, KLF4, IGF1R, FRS2, SFRP1, BCL2, BDNF and K-rasExogenous upregulation of miR-206 expression;STC2, HDAC4, KLF4, IGF1R, FRS2, SFRP1, BCL2, BDNF, and K-ras downregulated strongly in SCG-7901 cells overexpressing miR-206Gastric carcinoma SCG-7901 cells[303]
miR-206 is a potent tumor supressorReduced apoptosis, and cell migration in SCG-7901 cells overexpressing miR-206
Cyclin C, CCND1 and CDK4Cyclin C, CCND1 and CDK4 upregulated in melanoma tissue;hsa-miR-206 downregulated in melanoma tissueHuman melanoma cancer tissue, and cell lines[304]
Exogenous upregulation of miR-206 expression reduced growth and migration/invasion of several melanoma cell lines;Overexpression of miR-206 in melanoma cells strongly downregulated cyclin C, CCND1 and CDK4
G1 arrest in melanoma cells
Coronin, actin-binding proteinSilencing of coronin expression reduced tumor cell migration and altered the cellular actin skeleton and cell morphology, but did not effect cell proliferationDownregulated miR-206 allowed upregulation of coronin, a direct target;TNBC cell lines[305]
Upregulated miR-206 reduced TNBC cell migration and cell proliferation
RNA binding protein DEAD-END (DND1), DNA cytosine deaminase (AICDA), and APOBEC3DND1 blocks miRNA interaction with 3'-UTR of specific mRNAs, restores protein expression; APOBEC3G binds DND1 counteracts repression and restores miRNA activityAPOBEC3G blocks DND1 to restore miR-206 inhibition of CX43 translationMouse cells[306]
Advanced clinical stage, T classification, metastasis and poor histological differentiationSignificant association with decreased miR-206 expressionPaired human osteosarcoma and normal adjacent tissues[307]
Ellagic acid inhibits E2-induced mammary tumorigenesisReverses the downregulation of miR-206ACI model rat mammary tissue[308]
Actin-like 6A (BAF53a), a subunit of the SWI/SNF chromatin remodeling complexElevated BAF53aDownregulation of miR-206Primary rhabdomyosarcoma tumors[309]
Actin-like 6A (BAF53a)BAF53a transcript is significantly higher in primary rhabdomyosarcomas than in normal muscleRestoration of miR-206 expression downregulated BAF53a, which inhibits proliferation and anchorage independent growth;Primary rhabdomyosarcoma tumors[309]
BAF53a and is a direct target of miR-206
Wnt and transcription factors Tbx3 and Lef1Exogenous upregulation of miR-206 expressionInhibition of Wnt, Tbx3 and Lef1 activitiesEstrogen receptor alpha (ER-α)-positive human breast cancer; developing mammary buds[310]
ANXA2 and KRASStimulation of KRAS activity then induces NFKB1 expression;Downregulated miR-206 in PDACPDAC tissues and cell lines[311]
Induces NFKB1Increased KRAS results in stimulation of cytokines CXCR2, CXCL1, CCL2, as well as CSF2 (GM-CSF) and VEGFCIncreased cell cycle progression, cell proliferation, migration and invasion
Downregulated miR-1 and miR-133a
PNPPNP upregulatedReduced miR-1, -133aProstate cancer[97]
TAGLN2TAGLN2 upregulatedReduced miR-1, -133aRCC[136]
TAGLN2 and PNPTAGLN2 and PNP upregulatedReduced miR-1, -133aMSSCC[137]
PTMA and PNPPTMA and PNP upregulatedReduced miR-1, -133aBladder cancer (TCC)[312]
LASP1LASP1 upregulatedReduced miR-1, 133a, (and miR-218)Bladder cancer (TCC)[313]
Forced expression of each miR decreased LASP1 in cell lines
DNA methylation regulates miR-1-1 and miR-133a-2 cistron expressionInverse correlation with TAGLN2 levelsCpG islands upstream of miR-1-133a hypermethylatedColorectal carcinoma tissue and liver cancer tissue[314]
Downregulated miR-1 and miR-133b
miR-1 and mir-133b have sufficient power to distinguish recurrent specimens from non-recurrent prostate cancermiR-1 and mir-133b are significantly downregulated in recurrent prostate cancer tissue specimensRecurrent prostate cancer tissue[96]
Downregulated miR-1 and miR-206
NRF2 upregulatedDownregulated miR-1 and miR-206 expressionUpregulated expression of NRF2 induces increased expression HDAC4Primary lung adenocarcinoma; DU145 human prostate cancer cell line[99]
Loss of NRF2Decreased expression histone deacetylase (HDAC4)Results in increased expression of miR-1 and miR-206; which inhibits PPP expression; Reduced PPP acts as a regulatory feedback loop stimulates HDAC4 expressionA549 human NSCLC cell line[99]
c-Metc-Met upregulatedmiR-1 and -206 downregulatedHuman rhabdomyosarcoma[89]
ARPC5 and GSTP1ARPC5 and GSTP1 upregulatedReduced miR-133a (and miR-206)Lung SCC cell lines[115]
Downregulated miR-133a and miR-133b
PKM2PKM2 upregulatedDownregulated miR-133a, -133bTSCC[111]
FSCN1FSCN1 upregulatedDownregulated miR-133a, -133b, (miR-145)ESCC[132]
miR-133a, miR-133b downregulatedESCC[94]
KRT7KRT7 upregulatedDownregulated (miR-133a and miR-133b)Bladder cancer (TCC) and in vitro in BC KK47 cells[315]
Downregulated miR-1, miR-206 and miR-133
myomiRsPatient to patient variation in the up or down regulation of miR expression in both tumor and matched normal tissuesIn tumors strong down regulation of highly expressed miR-1/133a; (downregulation of weakly expressed miR-206/-133b)Bladder cancer assayed by deep sequencing[315]
Candidate tumor suppressor miRNAs in RCCEach of miR-206, miR-1, miR-133b strongly downregulatedRestored expression strongly inhibited cancer cell proliferation,RCC[316]
Shorter overall survival and disease-free survivalCorrelated with increased downregulated of miR-133b and/or miR-206Both miR-133b and miR-206 significantly downregulatedOsteosarcoma tissues[317]
Cell invasion and metastasismiR-1, miR-133a, miR-133b downregulatedmiR-133a, miR-133b involved in invasion and metastasisESCC[94]