Review Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Aug 26, 2015; 6(3): 162-208
Published online Aug 26, 2015. doi: 10.4331/wjbc.v6.i3.162
Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease
Keith Richard Mitchelson, Wen-Yan Qin, National Engineering Research Centre for Beijing Biochip Technology, Beijing 102206, China
Wen-Yan Qin, Medical Systems Biology Research Centre, Tsinghua University School of Medicine, Beijing 102206, China
Author contributions: Both authors contributed to this manuscript.
Supported by National High-tech Program of China, Nos. 2006AA020701 and 2009AA022701.
Conflict-of-interest statement: The authors declare no conflict of interests.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Dr. Keith Richard Mitchelson, National Engineering Research Centre for Beijing Biochip Technology, 18 Life Science Parkway, Zhonghuan Life Science Park, Beijing 102206, China.
Telephone: +86-10-61777524 Fax: +86-10-80726898
Received: April 11, 2014
Peer-review started: April 12, 2014
First decision: May 14, 2014
Revised: May 8, 2015
Accepted: May 27, 2015
Article in press: May 28, 2015
Published online: August 26, 2015


MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/tissue regeneration/tissue inflammation responses, and cancer development.

Key Words: Muscle microRNAs, MiR-1, MiR-206, MiR-133a, MiR-133b, Cell development, Cancer

Core tip: The roles of the canonical muscle-associated microRNAs are reviewed, including microRNA families miR-1 and miR-133, and single miR-206, which are collectively known as the “myomiRs”. The myomiRs act at the crossroads of the molecular regulation of muscle cells, linking between pathways for cell differentiation, development and maintenance, but also potentiate aberrant cell growth in numerous non-muscle cancers. Typically myomiRs are downregulated in cancers, but some myomiRs are upregulated in a few cancers, yet each dysregulation event advances tumor progression. The review examines normal and disease-linked molecular changes associated with the myomiRs, and collates the extensive literature into accessible tables.


MicroRNAs (miRs) are short single strand RNA molecules (typically 22 nt) which interact in a semi-complementary manner with numerous target gene mRNAs, directed by a short “seed sequence”, destining the targeted mRNA for degradation or for translational inhibition, and thus an miR can downregulate the functional expression of the target gene. In this manner a single miR can influence the abundance of numerous independent gene targets, and aid in the co-ordinate regulation of members of diverse cell signalling pathways, as well as metabolic pathways and basic cell proliferation or developmental processes. Three miR families, miR-1, miR-133 and miR-206 constitute the original (canonical) myomiRs and were considered muscle specific because of their prevalence in skeletal and cardiac muscle[1-5] and for their central roles in the regulation of myogenesis, muscle development and muscle remodelling[6-8]. Although other muscle enriched miRs such as miR-499 and -208, and others with key roles in cardiac muscle development have been identified, and although the term “myomiR” is now often used to denote several miRs encoded within myosin genes, for brevity this review is restricted to discussion of the three canonical myomiRs.

In man the genes encoding the canonical myomiR are organized into three cistrons encoding partners (miR-1-2, miR-133a-1), (miR-1-1, miR-133a-2) and (miR-133b, miR-206) and are located on chromosomes 18q11.2, 20q13.33 and 6p12.2, respectively. In this review we examine the roles of the myomiRs in normal tissue development and their emerging functions in various non-muscle tissues and their influence on the progression of cancers. The dysregulation of expression of the myomiRs in cancers is often related to a significant worsening patient prognosis, via the deregulation of a variety of validated gene targets.

The two mature miR-1 isomers have identical sequence, as have the two miR-133a isomers. The mature miR-133 isomers are also highly similar, differing only at the 3’-terminal base, with miR-133a1/2 terminating G-3’ and miR-133b with A-3’, respectively. Independent upstream enhancers have been identified for the cistronic miR-1-2 -133a-1 genes, as well as for the cistronic miR-1-1/-133a-2 genes which are intronic to the C20orf166 gene[9]. These independent enhancers allow the different isomer genes to be independently expressed under cell specific regulation.


MicroRNA-1 and -133 were initially identified during the development and differentiation of skeletal muscle[7] and cardiac muscle[2,6]. Both miR-1/-133a gene cistrons are canonically expressed in skeletal and cardiac muscle[5,9], whilst the miR-133b/-206 gene cluster is expressed in developing skeletal muscle[5] but not (significantly) in cardiac muscle, defining seminal roles of miR-1 and miR-133a in muscle biogenesis, and specifically in cardiac biogenesis[2,6]. A cartoon illustrating some of the major effects of myomiRs during differentiation of embryonic tissue and during tissue regeneration is shown in Figure 1.

Figure 1
Figure 1 The roles of the myomiRs during embryonic tissue differentiation and adult tissue regeneration. Elevated levels of miR-1 and miR-133a are essential for differentiation of cardiac muscle[10,15], whilst miR-1, miR-206 and miR-133b are required for skeletal muscle differentiation[7,13]. Elevation of miR-133b levels in adipose stem cells leads to differentiation to a nerve-cell like fate[71], whilst reduction in miR-133b leads to brown fat cell differentiation[74]. Strong depletion of miR-133b and elevated Fgf allows regeneration of damaged zebrafish appendages[67,68].

MiR-133a has a regulatory role from the earliest differentiation of myogenic stem cells into myoblasts[7,10] continuing throughout the growth of structurally complex muscle tissues[7,11], and has homeostatic functions for muscle maintenance and protection in mature muscle, or in muscle regeneration from muscle progenitor cells after skeletal muscle stress or injury[5]. Key studies show miR-1, -133b and -206 acting during early development of skeletal myocytes through to the homeostatic maintenance of skeletal muscle[3,4,8], with miR-133b/-206 also having functions in neuromuscular synapse development and maintenance[12], as detailed in Tables 1 and 2.

Table 1 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b.
Fish and lower vertebrates: Development and regeneration
Ttk protein kinase (mps1)Upregulated mps1: a target of miR-133Downregulation of miR-133 by FgfRegeneration of Zebrafish caudal fin (appendage)[68]
RhoADownregulation of RhoA mRNAUpregulation of miR-133b expressionRegenerating adult zebrafish spinal cord, axon outgrowth[69]
RhoADownregulation of RhoA proteinUpregulation of miR-1 and miR-133 expressionZebrafish muscle gene expression and regulation of sarcomeric actin organization[166]
Cell cycle factors mps1, cdc37 and PA2G4, and cell junction components cx43 and cldn5Upregulated mps1, cdc37, PA2G4, cx43, cldn5Downregulated miR-133(a1) stimulates cardiac cell regenerationRegenerating zebrafish cardiac muscle[167]
miR-133bMiR-133b found in developing somites, little in CNS tissuesWhole zebrafish embryos - normal development[168]
SRF activates muscle specific genes and miRs;MiR-1 targets HDAC4, promoting myogenesisIn contrast, miR-133a represses SRF, enhancing myoblast proliferationX. laevis embryos: skeletal muscle proliferation and differentiation in cultured myoblasts in vitro and in embryos in vivo[7]
HDAC4 represses muscle gene expression
nAChR subunits UNC-29, UCR-63; MEF2Subunits UNC-29, UCR-63, and MEF2 downregulatedmiR-1 upregulatedC. elegans muscle at the neuromuscular junction[34]
Mammalian pluripotent cells
Muscle-specific microRNAs: miR-1 and miR-133aMiR-1 and miR-133a have opposing functions during differentiation of progenitor cardiac musclesMuscle-specificPromotion of mesoderm formation from mouse ES cells[13]
microRNAs, miR-1 and miR-133(a) upregulated
Notch signalling, promotes neural differentiation and inhibits muscle differentiation; opposes miR-1 effectsDll-1 translationally repressedmiR-1 upregulation, promotes cardiomycete differentiationMouse and human ES cell differentiation into muscle[13]
SRF-/- EBs reflecting the loss of hematopoietic lineages in the absence of SRFEarly endoderm markers, Afp and Hnf4α: strongly down regulatedIncreased miR-1 and miR-133a relieve the block on mesodermal differentiationMouse endoderm[13]
Blood cell -specific genes, such as Cd53, CxCl4, and Thbs1, dramatically down regulatedCd53, CxCl4, and Thbs1 expression was reinitiated by reintroduction of miR-1 or miR-133
mES(miR-1)- and mES(miR-133a)- EBs compared to in control EBsNodal stimulated expression of endoderm markers Afp and Hnf4α in control EBs. Dramatically lower levels in mES(miR-1)- and mES(miR-133a)- EBsmiR-1 or miR-133 can each function as potent repressors of endoderm gene expressionmES cells, that lack either miR-1 or miR-133(a) during differentiation into EBs[13]
IGF-1IGF-1 signalling and miR-133 co-regulate myoblast differentiation via a feedback loopIGF-1 upregulates miR-133;Myogenic differentiation of C2C12 myoblasts; Mouse during development from embryonic to mature skeletal muscle[24]
IGF-1RmiR-133 downregulates IGF-1R
IGF-1IGF-1 signalling and miR-1 coregulate differentiation of myoblasts via a feedback loopIGF-1 signalling downregulates miR-1 by repression of FoxO3a;Differentiating C2C12 myoblasts[25]
miR-1 down-regulates IGF-1
Reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine]Decrease in active histone modifications; including trimethylation of histone H3K4/ H3K36, phosphorylation of H3S10;miR-133a expression strongly inhibited by reversine; reduced acetylation of H3K14 at miR-133a promoterReversine dedifferentiates murine C2C12 myoblasts back into multipotent progenitor cells, via extensive epigenetic modification of histones resulting in chromatin remodelling, and altered gene expression[20-23]
Stimulates expression of polycomb genes Phc1 and Ezh2Reduced expression of myogenin, MyoD, Myf5 and Aurora A and B kinases
FZD7 and FRS2miR-1 promotes cardiac differentiation; miR-1 targets FZD7 and FRS2Activitation of WNT and signalling cause MCPs differentiation into cardiomyocytesMouse and human ES cells[169]
miR-206/133b clusterPAX7 gene expression unchanged;miR-206/133b cistron knock-out mice cellsMuscle satellite cell differentiation in vitro[170]
miR-206/133b cluster is not required for development, and survival of skeletal muscle cells
Differentiating skeletal muscle
DNA polymerase alphaRepression of Idl-3 protein expressionmiR-206 up-regulatedMouse skeletal muscle differentiation[42]
Repression of p180 subunit of DNA polymerase alpha
MEF2 transcription factorMEF2 activates of miR-1-2 and 133a-1 transcription; binds muscle-specific enhancerBicistronic primary transcript of miR-1-2 and 133a-1Development of mammalian skeletal muscle[9]
MRFs, Myf5, MyoD, Myogenin and MRF4Myf5 essential for miR-1 and miR-206 expression during skeletal muscle myogenesisForced expression of MRFs in neural tube induces miR-1 and miR-206 expressionChicken and mouse embryonic muscle[171]
PTB and neuronal homolog nPTB, exon splicing factorsDownregulation of PTB protein by miR-133 (and miR-206)Concurrent upregulation of miR-133 and induction of splicing of several PTB-repressed exonsDuring myoblast differentiation, microRNAs control a developmental exon splicing program[172]
BDNFBDNF downregulatedmiR-206 upregulatedDifferentiation of C2C12 myoblasts into myotubes[48]
Fstl1 and UtrnFstl1 and Utrn downregulatedmiR-206 upregulatedSkeletal muscle differentiation[40]
Utrophin A (muscle)Utrophin A down-regulated by both miRsUpregulated miR-133b, miR-206C2C12 mouse myoblasts, mouse soleus muscle[173]
CNN3 geneNegative correlation between miR-1 expression and CNN3 mRNA expressionNormal skeletal muscleTongcheng (Chinese) and Landrace (Danish) pigs[174]
FGFR1 and PP2AC, members of ERK1/2 signalling pathwaymiR-133 (a and b) activities increase during myogenesismiR-133 directly downregulates expression of FGFR1 and PP2ACMouse C2C12 myoblast cells[31]
ERK1/2 signalling pathway activityERK1/2 signalling activity suppresses miR-133 expressionDownregulation of expression of miR-133A reciprocal mechanism for regulating myogenesis
BAF chromatin remodelling complex (BAF60a, BAF60b and BAF60c)Positive inclusion of BAF60c in the BAF chromatin remodeling complexExpression of miR-133 and miR-1/206Progression of developing somites in chick embryos[63]
BAF chromatin remodelling complexNegative regulation of BAF60a and BAF60b; exclusion from BAF chromatin remodelling complexExpression of miR-133Progression of developing somites in chick embryos[63]
BAF chromatin remodelling complexExogenous upregulation of BAF60a and BAF60bDelay in developing somites in chick embryos[63]
Mitochondrial UCP2 and UCP3MyoD activates miR-133a expression which in turn directly downregulates UCP2 mRNAFeedback network involving MyoD-miR-133a-UCP2Mouse skeletal and cardiac muscles; UCP2 imposes developmental repression[56]
Mitochondrial UCP2 and UCP3Exogenous overexpression of myogenin and MyoD transcription factorsStrong increase in UCP3 promoter, expression, weak effect at the UCP2 promoterMouse C2C12 myoblasts[57]
Proliferating myogenic skeletal muscle cells
MiR-206/133b clusterMiR-206/133b cluster is not required for survival and regeneration of skeletal muscleMuscle regeneration proceeds in Mdx mice in vivomiR-206/133b cistron knock-out mice[170]
Enhanced translation of specific mitochondrial genome-encoded transcriptsmiR-1 enters muscle mitochondria and binds mtRNA targets along with Ago factorIncreased expression of mtRNA targetsProliferating myogenic skeletal muscle cells after muscle injury[53]
mTOR (serine/threonine kinase)MyoD stability regulated by mTORRegulates miR-1 expression via MyoD availabilityRegenerating mouse skeletal muscle and differentiating myoblast cells[32]
AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathwaysmTORC regulates timing of satellite cell proliferation during myogenesisKnockdown of mTORC reduces miR-1 expressionMyogenenic satellite SCs proliferating and differentiating into myogenic precursors following rat skeletal muscle injury[58]
HDAC4 regulates Pax7-dependent muscle regenerationPax7 stimulates SCs differentiation toward the muscle lineage, and limits adipogenic differentiationHDAC4 upregulated in SCs differentiating into muscle cellsMyogenenic satellite SCs[175]
pcRNA encoded by the H strand of the rat mitochondrial genomeIntroduction of mt pcRNAs into injured muscle restoring mitochondrial mRNA levels; Intramuscular ATP levels were elevated after pcRNA treatment of injured muscleEnhanced organellar translation and respiration; similarly reactive oxygen species were reduced; Resulted in accelerated rate of wound resolutionInjured rat skeletal muscle is associated with general downregulation of mitochondrial function; reduced ATP, and increased ROS[176]
Cardiac muscle precursor cells
GATA binding protein 4, Hand2, T-box5, myocardin, and microRNAs miR-1 and miR-133Reprogrammed human fibroblasts show sarcomere-like structures and calcium transients; Some cells have spontaneous contractilityForced over-expression of GATA binding protein 4, Hand2, T-box5, myocardin, and microRNAs miR-1 and miR-133Human embryonic and adult fibroblasts activated to express cardiac markers[15]
SRF, MyoD and Mef2 transcription factorsmiR-1-1 and miR-1-2miR-1 genes upregulated;Cardiac muscle precursor cells[30]
During cardiogenesis miR-1 genes titrate critical cardiac regulatory proteins, control ratio of differentiation to proliferationElevated miR-1 targets downregulation of Hand2
Histone deacetylase inhibitor, trichostatin A forces differentiation, yet reduced miR-1 and miR-133amiR-1 and miR-133a reduce cardiac specific Nkx2.5 protein and Cdk9miR-1 and miR-133a increase during spontaneous differentiation of cardiac myoblastsMouse cardiac stem cells (ES cells)[10]
Specific inhibition of HDAC4 modulates CSCs to facilitate myocardial repairPositively proliferative myocytes increased in MI hearts receiving HDAC4 downregulated CSCsCSCs with downregulated HDAC4 expression improved ventricular function, attenuated ventricular remodeling, promoted regeneration and neovascularization in MI heartsMouse CSCs transplanted into MI mouse hearts[177]
Snai1Overexpression of miR-133a (miR-133), Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and MyocD improved cardiac cell reprogramming from mouse or human fibroblastsmiR-133a directly represses Snai1 expression, which silences fibroblast signatures; a key molecular process during cardiac reprogrammingMouse/human fibroblasts more efficiently reprogrammed into cardiomycete-like cells[16]
β1AR signal transduction cascadeAdenylate cyclase VI and the catalytic subunit of the cAMP-dependent PKA are components of β1AR transduction cascademiR-133 directly targets β1AR, Adenylate cyclase VI and PKATetON-miR-133 inducible transgenic mice, subjected to transaortic constriction, maintained cardiac performance with attenuated apoptosis and reduced fibrosis via elevated miR-133 expression[17]
ROS, MDA, SOD and GPxmiR-133 produced a reduction of ROS and MDA levels, and an increase in SOD activity and GPx levelsOverexpression of miR-133, a recognized anti-apoptotic miRNAIn vitro rat cardiomyocytes[18]
Caspase-9miR-133 directly suppresses caspase-9 expression resulting in downregulation of downstream apoptotic pathwaysOverexpression of miR-133In vitro rat cardiomyocytes[18]
Spred1miR-1 directly targets Spred1miR-1 is upregulated in hCMPCs during angiogenic differentiationhCMPCs[178]
miRNA-1 and miRNA-133amiRNA-1 and miRNA-133a have antagonistic roles in the regulation of cardiac differentiationForced overexpression of miR-1 alone enhanced cardiac differentiation, in contrast overexpression of miR-133a reduced cardiac differentiation, compared to control cellsPluripotent P19.CL6 stem cells[179]
Overexpression of both miRNAs promoted mesodermal commitment and decreased expression of neural differentiation markers
Cardiac muscle
Induction of GATA6, Irx4/5, and Hand2Cardiac myocytes show defective heart development, altered cardiac morphogenesis, channel activity, and cell cyclingmiR-1-2-/- gene knockoutCardiac myocytes with knockout of both miR-1-2 genes[180]
mt-COX1 mRNA3’-UTR of mt-COX1 mRNA bound by miR-181c and Ago1 factorOverexpression of miR-181c significantly decreased mt-COX1 protein, but not mt-COX1 mRNA levelOverexpression of miR-181c increased mitochondrial respiration and reactive oxygen species in neonatal rat ventricular myocytes[54]
mt-COX1 mRNAIn vivo elevation of miR-181c in rat heart, reduces levels of mt-COX1 proteinResults in reduced capacity for strenuous exercise and evidence of heart failureRat cardiac muscle[55]
Carvedilol, a β-adrenergic blockerInduces upregulation of miR-133Cytoprotective effects against cardiomyocyte apoptosisRat cardiac tissue, in vivo[18]
GLUT4, and SRFBoth miRs downregulate SRF and KLF15Both miR-133a and miR-133b target KLF15Mouse cardiac myocytes[181]
GLUT4 expressionBoth basal and insulin-stimulated glucose uptake are increasedKLF15Mouse muscle cell lines[182]
MEF2 transcription factorMEF2 directly activates transcription of miR-1-2 and 133a-1 binding muscle-specific enhancer between the genesBicistronic primary transcript of miR-1-2 and 133a-1Development of mammalian cardiac muscle[9]
Myocardium tissueEnriched in miR-1, miR-133b, miR-133aHeart structures of rat, Beagle dog and cynomolgus monkey[183]
GelsolinOne common miR-133a isomiR targets gelsolin gene more efficiently than standard isomer; New second rat miR-1 geneMany isomiRs were detected by deep sequencing at higher frequency than the canonical sequence in miRBasemiRNA/isomiR expression profiles in the left ventricular wall of rat heart[184]
CTGFCTGF downregulated by both miRsExogenous upregulation of miR-133b (and miR-30c)Cultured cardiomyocytes and ventricular fibroblasts[185]
MT1-MMPmiR-133a upregulatedmiR-133a targets MT1-MMPHuman left ventricular fibroblasts[186]
Injured and regenerating cardiac muscle
SERCA2aAkt/FoxO3A-dependent pathwayDownregulation of miR-1 expression in failing heart muscleFailing mouse heart muscle[187]
Activated SERC2a reduces phosphorylation of FoxO3a, allowing entry to nucleus and activation of miR-1 expression
IGF-1IGF-1 signalling and miR-1 co-regulate differentiation of myoblasts via a feedback loopIGF-1 signalling down-regulates miR-1 by repression of FoxO3a;Mouse heart muscle during cardiac failure states[25]
miR-1 down-regulates IGF-1
Bim and BmfOnly miR-133a expression enhanced under in vitro oxidative stressmiR-133a targets proapoptotic genes Bim and BmfRat adult CPCs[188]
miR-1 favors differentiation of CPCs, whereas
Bim and BmfCPCs overexpressing miR-133a improved cardiac function by reducing Bim and BmfCPCs overexpressing miR-133a improved cardiac function, increasing vascularization and cardiomyocyte proliferation, reduced fibrosis and hypertrophyCPCs overexpressing miR-133a in rat myocardial infarction model[188]
MT1-MMP activity increased in both. Ischemia and reperfusion regionsInterstitial miR-133a decreased with ischemia in vitro and in vivo; reperfusion returned to steady-statePhosphorylated Smad2 increased within the ischemia-reperfusion regionIschemia-reperfusion Yorkshire pigs (90 min ischemia/120 min reperfusion)[186]
Cardiovascular disease
CNN2Strong upregulation of CNN2 expressionmiR-133b downregulated; miR-133b directly targets CNN2Pre-inflammatory events in diseased cardiac tissues[65]
Circulating platelet derived microparticlesElevated miR-133Patients with stable and unstable coronary artery disease[189]
Acute MI causes upregulation of circulating serum miRsmiR-1, -133a, -133b, and -499-5p were about 15- to 140-fold elevated over controlAcute STEMI patients and experimental mouse MI model[190]
Circulating miRNAs in serum of cardiovascular disease patientsReleased miR-1 and miR-133a are localized in exosomes, and are released by Ca(2+) stimulationLevels of miR-1, miR-133a, reduced in infarcted mouse myocardium model heartmiR release indicates myocardial damage[191]
LVM after valve replacement in aortic stenosismicroRNA-133a is a significant positive predictor of LVM normalisationmiR-133 is a key element of the reverse remodelling processPatients following valve replacement[192]
Circulating levels of miR-133aElevated miR-133a (11-fold)Troponin-positive acute coronary syndrome patients[193]
Circulating levels of miR-133aElevated miR-133aImproved potential regression of Left Ventricular Hypertrophy after valve replacementPatients with aortic stenosis surgery[194]
Apelin treatment reduces elevated circulating miRsElevated miR-133a, miR-208 and miR-1 reducedHigh-fat diet elevated miRs and increased left ventricular diastolic and systolic diameters, and wall thicknessObesity-associated cardiac dysfunction in mouse model[195]
NAC treatmentExpressed miR-1, miR-499, miR-133a, and miR-133b were strongly depressed in the diabetic cardiomyocytesNAC restored expression of miR-499, miR-1, miR-133a, and miR-133b significantly in the myocardiumDiabetic rat hearts[196]
Myocardial junctin elevatedmiR-1 targets junctinNAC reduces junction levelsDevelopment of diabetic cardiomyopathy in rat hearts[196]
CAD associated ischemic heart failuremiR-133 expression decreased with increased severity of heart failurePatients with CAD[197]
Runx2miR-133a targets Runx2Transition of VSMCs to osteoblast-like cells[198]
Increased alkaline phosphatase activity, osteocalcin secretion and Runx2 expressionmiR-133a was decreased during osteogenic differentiationTransition of VSMCs to osteoblast-like cells[198]
Circulating miR-133a and 208a levelsCardiac muscle-enriched microRNAs (miR-133a, miR-208a) elevatedPatients with coronary artery disease[199]
Hypertrophic cardiac muscle
Cx43 increasedmiR-1 targets Cx43Downregulation of miR-1 mediates induction of pathologic cardiac hypertrophyHypertrophic rat cardiomyocytes in vitro and in vivo[200]
Cx43 downregulatedmiR-1 targets Cx43Cx43 protein downregulated in miR-1 Tg mice compared to WT miceCardiac-specific miR-1 transgenic (Tg) mouse model[201]
Twf1 upregulatedmiR-1 targets Twf1Strong downregulation of miR-1 in pathologic hypertrophic cardiac cells compared to normal, induces Twf1 expressionIn vivo in hypertrophic mouse left ventricle; and in vitro in phenylephrine-induced hypertrophic cardiomyocytes[202]
RhoA, Cdc42, Nelf-A/WHSC2Increased levels of RhoA, Cdc42, Nelf-A/WHSC2Reduction miR-133aHypertrophic cardiac muscle[6]
Calcineurin, agonist of cardiac hypertrophyIncreased Calcineurin activity;Reduced miR-133a;Hypertrophic cardiac muscle;[203]
Cyclosporin A inhibits calcineurinPrevents miR-133 down-regulationCardiac hypertrophy reduced
NFATc4NFAFc4 targetted by miR-133amiR-133aCardiomyocyte hypertrophic repression[204]
Interdependent Calcineurin-NFAT and MEK1-ERK1/2 signalling pathways in cardiomyocytesMEK1-ERK1/2 signalling augments NFAT and NFAF gene expression; Activated calcineurin activates NFAT, inducing cardiac hypertrophyMEK1 is part of mitogen-activated protein kinase (MAPK) cascade; MEK1 activates ERK directlyHypertrophic growth response of mouse cardiomyocytes[205]
Innervating skeletal muscle
Innervated skeletal muscleMyoD, Myf5, Mrt4, nAChRαMyogenin expressionMouse skeletal muscle[50,51]
Each is strongly repressed
Denervated muscle (unstimulated)Myogenin expression up-regulated MyoD, Myf5, Mrt4, nAChRαMouse skeletal muscle[51]
All strongly stimulated
Electrically stimulated - Denervated muscleMyogenin, MyoD, Myf5, Mrt4, partly stimulated; nAChRα inhibitedMouse skeletal muscle[51]
HDAC4miR-1 promotes myogenesis by targetting HDAC4miR-133 enhances myoblast proliferation by targetting SRFSkeletal muscle proliferation and differentiation in myoblast cultures[7]
Neural activity effect on muscle (HDAC4 - MEF2 Axis)Loss of neural input leads to concomitant nuclear accumulation of HDAC4HDAC4 inhibits activation of muscle transcription factor MEF2; results in progressive muscle dysfunctionMEF-2 activity strongly inhibited in denervated mouse skeletal muscle and in ALS muscle[49]
Innervation and formation of airway smooth muscleSonic hedgehog (Shh) /miR-206/ BDNFShh signalling blocks miR-206 expression, which in turn increases BDNF proteinShh coordinates innervation and formation of airway smooth muscle[206]
nAChR subunits (UNC-29 and UNC-63); retrograde signallingSubunits UNC-29, UCR-63 and MEF2 downregulatedmiR-1 upregulatedC. elegans muscle at the neuromuscular junction[34]
MEF2Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulatedmiR-206 upregulatedRat skeletal muscle/re-innervating muscle[43]
HDAC4HDAC4 (miR-206 target, prospective miR-133b target) downregulatedmiR-206/-133b upregulated (and miR-1/-133a downregulated)Mouse fast twitch skeletal muscle/re-innervating muscle[12]
Regenerating injured muscle
Hnrpu and Npy downregulatedmiR-1 upregulatedmiR-1, -133a, downregulated 1 mo after denervation, then increased 2 × at 4 mo after re-innervationRat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation[43]
Ptprd downregulatedmiR-133a upregulated
Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulated3 × increase in miR-206 1 mo later, after reinnervation; elevated at least 4 moPredominant type II fiber at 4 mo, after nerve re-innervationRat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation[43]
PP2A B56aPP2A B56a downregulated133a upregulatedCanine heart failure model: myocytes[207]
CaMKII-dependent hyperphosphorylation of RyR2VF myocytes had increased reactive oxygen species and increased RyR oxidationmiR-1 upregulatedCanine post-myocardial infarction model[208]
Collagen upregulatedTGF-b1 and TGFbRII: upregulatedmiR-133a or miR-590: downregulatedCanine model of acute nicotine exposure. Atrial fibrosis in vivo; cultured canine atrial fibroblasts in vitro[209]
miR-208 upregulatedmiR-1 and miR-133a downregulatedHuman MI compared to healthy adult hearts[210]
Myogenic proteins, MyoD1, myogenin and Pax7Induced expression of MyoD1, myogenin and Pax7 several days after miR injectionExogenous injection of miR-1, -133 and -206 promotes myotube differentiationRegenerating injured mouse skeletal muscle[211]
Cyclin D1/ Sp1Cyclin D1/ Sp1 downregulatedmiR-1/133 upregulatedRegenerating rat skeletal muscle[212]
PRP, source of pro-inflammatory cytokinesStong upregulation of the mRNA of pro-inflammatory cytokines IL-1β and TGF-β1; stimulation of both inflammatory and myogenic pathways; elevated heat shock proteins and increased phosphorylation of αB-cristallinStimulated tissue recovery via increased myogenic regulators MyoD1, Myf5, Pax7, and IGF-1Eb (muscle isoform) together with SRF; acts via increased expression of miR-133a with reduced levels of apoptotic factors (NF-κB-p65 and caspase 3)Regenerating flexor sublimis muscle of rats, 5 d after injury and treated with PRP[66]
Muscle degeneration
Pro-inflammatory cytokine TWEAKTWEAK upregulatedmiR-1-1, miR-1-2, miR-133a, miR-133b and miR-206 downregulatedDegenerating/wasting mouse skeletal muscle[59]
HMOX1 mediated by codependent inhibition of c/EBPδ binding to myoD promoterHMOX1 inhibits differentiation of myoblasts and modulates miRNA processingDownregulation of miR-1, miR-133a, miR-133b, and miR-206.Degenerating/wasting mouse skeletal muscle[60]
HMOX1 effects partially reversed by enforced expression of miR-133b and miR-206Downregulation of MyoD, myogenin and myosin, and disturbed formation of myotubes. Upregulation of SDF-1 and miR-146a
Dystrophic muscular disease
Circulating serum microRNAsmiR-1, miR-133a, and miR-206 highly abundant in Mdx serummiR-1, miR-133a, and miR-206 downregulated or modestly upregulated in muscleMuscle tissue from patients with Duchenne muscular dystrophy (Mdx)[213]
Laminin α2 chain deficiencymiR-1, miR-133a, and miR-206 are deregulated in laminin α2 chain-deficient muscleLaminin α2 chain-deficient mouseCongenital muscular dystrophy type 1A tissue[214]
Dystrophic process advances from prominent inflammation with necrosis and regeneration to prominent fibrosisDeficiency in calpain leads initially to accelerated myofiber formation followed by depletion of satellite cellsPax7-positive SCs highest in the fibrotic patient group; correlated with down-regulation of miR-1, miR-133a, and miR-206Muscle from Limb-girdle muscular dystrophy 2 type I patients[215]
Transgenic overexpression of miR-133a1 (in dystrophin point mutation Mdx mice)Extensive overexpression in skeletal muscle, lesser increase in heartNormal skeletal muscle and heart developmentMdx mice (model for human muscular dystrophy), extensor digitorum longus muscle[216]
miR-206 located in nuclear in both normal and DM1 tissues by in situ hybridizationOnly miR-206 showed an over-expression in majority of DM1 patientsNo change in expression of profiled miRs, miR-1, miR-133 (miR-133a/-133b), miR-181 (miR-181a/-181b/-181c)Skeletal muscle (vastus lateralis) of from patients with myotonic dystrophy type 1 (DM1)[217]
FAPs facilitate myofiber regenerationHDAC inhibitors can activate FAPs towards muscle regenerationInhibition of HDAC induces MyoD and BAF60C expression, which causes up-regulation of miR-1-2, miR-133, and miR-206 expressionEarly stage disease dystrophic mouse muscles, regeneration of myofibres[62]
TDP-43TDP-43 interacts with miR-1/-206 isomers, but not miR-133 isomersDepleted miR-1/-206 allow targets IGF-1 and HDAC4 to accumulate in ALS muscleMouse ALS model injured motor neurons and muscle[33]
Inflammation response in muscle
Inflammatory myopathiesIncreased expression of TNFαAssociated with decreased expression of miR-1, miR-133a, and miR-133bInflammatory myopathies including dermatomyositis, polymyositis, and inclusion body myositis[64]
hBSMCs sensitized with IL-13Increased muscle RhoAReduction of muscle miR-133aSensitized human bronchial smooth muscle cells (hBSMCs)[218]
Table 2 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b in other precursor cells and tissues.
Nerve tissues
Pitx3Pitx3 downregulatedmiR-133bMammalian midbrain DNs[73]
Exosome-mediated transfer of miR-133b from MSC to brain astrocytesmiR-133b transfer from multipotent mesenchymal stromal cells to neural cellsmiR-133b upregulatedMouse MSCs to neural cells[47]
Ctgf and RhoACtgf and RhoA downregulatedmiR-133b upregulatedMultipotent MSCs/Rat brain parenchymal cells[72]
miR-133b null mice: Striatum dopamine levels unchanged, Pitx3 expression unaffected; motor coordination unalteredmiR-133b has no significant role on mDA neuron development and maintenance in vivoNormal numbers of mDA neurons during development and aging of miR-133b null miceMouse mDA neuron development in -/-miR-133b mutant mice[45]
Acute or chronic morphine administration, or morphine withdrawalmiR-133b levels not affectedRat VTA/ nucleus accumbens shell[219]
GPM6A, a neuronal glycoproteinmicroRNA-133b upregulationReduction in gmp6a at mRNA and protein level. Cell filopodium density was reducedHippocampus and prefrontal cortex of neonatal male rats stressed when in utero[220]
Tac1 gene (neurotransmitter substance P)Tac1 downregulatedmiR-206 upregulatedMSCs-derived neural cells[221]
Ketamine (antidepressive) administrationBDNF, a direct target gene of miR-206, was upregulatedmiR-206 was downregulated by ketamineRat hippocampus tissue[222]
Adipogenic tissues
IGF-1 and IGF-1RIGF-1 signalling and miR-133b co-regulate ADSC differentiation via a feedback loopmiR-133b downregulation of Pitx3;Adipose tissue-derived stem cell differentiation into neuron-like cells[71]
IGF-1 upregulates miR-133b;
miR-133b downregulates IGF-1R
Pdrm16miR-133a directly targets Prdm16.Downregulation of miR-133 resultsin differentiation of pre-adipocyte precursors into BATMouse adipocyte differentiation to BAT[74]
Pdrm16miR-133 directly targets Prdm16Downregulation of miR-133 resulted in differentiation of pre-adipocyte precursors into BATMouse primary brown adipocyte (and myogenic) progenitor cells - differentiate into BAT or SAT[75]
Pdrm16miR-133 targets Prdm16 controlling brown adipose determination in skeletal muscle satellite cellsmiR-133 downregulates Prdm16Adult mouse skeletal muscle stem cells (satellite cells) differentiate into BAT[76]
HDAC4 downregulation directs SCs towards adipocyte differentiationBrown adipose master regulator Prdm16 is upregulated, while its inhibitor miR-133 is also downregulatedHDAC4 downregulated in SCs differentiating into adipocyte progenitor cellsMyogenenic satellite SCs[175]
GLUT4 expressionBoth basal and insulin-stimulated glucose uptake are increasedKLF15Mouse 3T3-L1 preadipocytes differentiating into adipocytes[182]
Intrinsic insulin resistanceElevated miR-133bUndefined roleAdipose tissue of women with PCOS[223]
Upregulation of LIM homeobox 8 and Zic family member 1 and downregulation of Homeobox C8 and Homeobox C9Undefined relation of upregulated miR-206, miR-133bUndefined relation with parallel upregulation of brite/beige markers, TBX1 and TMEM26Human BAT from the supraclavicular region[224]
Obesity developmentDownregulation of miR-133b, miR-1Undefined roleAdipose tissue from obese male C57BLJ6 mice[225]
LXRα regulation of lipogenic genesmiR-1/miR-206 represses LXRα expression at both mRNA and protein levelsmiR-1/miR-206-induces a decrease in lipogenic gene levels and lipid droplet accumulationMouse hepatocytes[226]
Osteogenic tissues
Development of bone on organic or inorganic substratesmiR-133 differentially expressed in osteoblasts grown on different substratesOsteoblast[227]
Runx2miR-133 directly down-regulates Runx2miR-133 up-regulatedOsteogenic differentiation from C2C12 mesenchymal cells[228]
HDAC4HDAC4 downregulates Runx2miR-1 targets HDAC4, increasing Runx2 activityChondrocyte proliferation in cartilage growth plate[77]
AggrecanmiR-1 promotes late-stage differentiation of growing cartilage cellsmiR-1 targets Aggrecan gene expressionChicken chondrocytes and human HCS-2/8 cells[78]
Alveolar cells
VAMP2/ lung surfactant secretionmiR-206 targets VAMP-2miR-206 overexpression decreased lung surfactant secretionLung alveolar type II cells[229]
Hormonal regulation
L-thyroxinemiR-206/miR-133b downregulatedL-thyroxine treatmentL-thyroxine treated hypothroidic skeletal muscle from thyroidectomized patients[230]
miR-206/miR-133b upregulated-Hypothroidic human skeletal muscle
Thyroid hormone/TEAD1Thyroid hormone inhibits the slow muscle phenotype by upregulation of miR-133a1 which downregulates TEAD1miR-133a1 is enriched in fast-twitch muscle and regulates slow-to-fast muscle fiber type conversionMouse muscle[231]
Thyroid hormone/miR-133a1 TEAD1myosin heavy chain I expression downregulatedTH indirectly downregulates myosin heavy chain I via miR-133a/TEAD1Mouse muscle[232]
L-thyroxinepre-miR-206 and pre-mir-133b downregulatedL-thyroxineL-thyroxine treated hypothyroidic mouse liver;[232]
50-500x increase expression of miR-1/-133a and miR-206/-133b-Hypothyroidic mouse liver
Reduced insulin-mediated glucose uptake in cardiomycetesDownregulation KLF15, which downregulates GLUT4Forced overexpression of miR-133a and miR-133bRat cardiac myocytes[181]
Cardiac myocyte glucose metabolismUpregulation KLF15, which upregulates GLUT4Silencing endogenous miR-133Rat cardiac myocytes[181]
Metabolic control of glucose uptake by GLUT4 transporterDownregulates KLF15, which results in downregulation of GLUT4 levelsChronic heart failure has depressed miR-133a and -133b levelsRat cardiac myocytes during chronic heart failure and cardiac hyperthrophy[181]
Atrial natriuretic factor expression upregulationEnhanced at LVH and dramatically increased at CHF stageBoth miR-133a and miR-133b downregulated at CHF stageLVH and CHF in salt-sensitive Dahl rats[181]
EstrogenEstrogen replacement strongly decreased IGF-1 protein level in muscles at 1 wkOvariectomized rat skeletal muscle[233]
Multiple targetsmiR-133a upregulated in BTBR micePancreatic islets, adipose tissue, and liver from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mice[234]
Augmentation of adipocyte differentiation by norepinephrine does not alter myomiR levelsmiRNAs miR-1, miR-133a and miR-206 specifically expressed both in brown pre- and mature adipocytesmiRNAs miR-1, miR-133a and miR-206 were absent from white adipocytesMouse brown adipocytes[235]
Foxl2miR-133b targets Foxl2;Foxl2 regulates StAR and CYP19A1 transcriptionallyEstradiol production in ovarian granulosa cells[236]
miR-133b inhibits Foxl2 binding to StAR and CYP19A1 promoter sequences
Exosome release and cell to cell transfer
Exosome-mediated transfer of miR-133b from MSCs to brain astrocytesmiR-133b transfer from multipotent mesenchymal stromal cells to neural cellsmiR-133b upregulatedMouse multipotent MSCs to neural cells[47]
Cell to cell transfer of exosome-enriched extracellular particlesmir-133b promotes neural plasticity and recovery of function after stroke induced damagemiR-133b upregulatedRat multipotent MSCs via transfer of exosome-enriched extracellular particles[72]
Transplanted stem cells
MSCs expressing miR-1Upregulated miR-1Increased rate of recovery, enhanced survival of transplanted MSCs and cardiomyogenic differentiationExperimental ligation of the mouse left coronary artery to model myocardial infarction[237]
Knockdown of Hes-1, member of Notch pathwayUpregulated miR-1 promotes the differentiation of MSCs into cardiac lineageRole in survival of transplanted MSCs and cardiomyogenic differentiationMouse MSCs[238]
Notch signalling and cardiomyocyte markers, Nkx2.5, GATA-4, cTnT, and Cx43MSCs expressing exogenous miR-1Mouse MSCs[238]
Tissue inflammation
Selective release of miRs during inflammation into serummiR-133 selectively releasedReview[239]
Inflammation and cancerMicroRNA, free radical, cytokine and p53 pathwaysReview[240]
Immunological switch which shapes tissue responsesTWEAK/Fn14 pathwayReview[241]
Tumor biologyHMOX1Review[242]
GM-CSFDirect supression of GM-CSF expression by miR-133Elevated expression of miR-133a/-133b during oxidative stressMouse alveolar epithelial cells during oxidative stress[82]
PI3K/Akt and IGF-1 pathwaysActivation of PI3K/Akt and IGF-1 pathway activitiesDownregulation of miR-133a (and other miRs) by AOM/DSS induced chronic inflammationMouse model: AOM/DSS-induced colitis-associated gastro-intestinal cancer[83]
CTGF, SMA, and COL1A1Increased expression of CTGF, SMA and COL1A1, which are miR-133b targetsStrong downregulation of miR-133b (and other miRs)TGF-β treated rabbit corneal fibroblasts; Recovering mouse cornea after laser ablation,[70]
IL-10 and TGF-βExogenous IL-10 and TGF-β induces miR-133b expressionUpregulation of miR-133bHuman tolerogenic dendritic cells during maturation[79]
IL-17-producing T-cellsUpregulation of Il17a/f gene expressionmiR-133b/-206 cistron transcription occurs along with nearby Il17a/f gene expressionImmunocompetent mouse Th17 cells[80]
NLRP3 inflammasome which processes IL-1β by caspase-1 cleavagemiR-133a-1 suppresses activation of inflammasomes via suppression of expression of mitochondrial UCP2miR-133a-1 overexpression in cells increases caspase-1 p10 and IL-1β p17 cleavage,Differentiated mouse THP1 cells[81]
Concanavalin A-induced fulminant hepatitismiR-133a is the most strongly differentially upregulated miRMouse liver following ConA injection[243]
Infection/immune response to influenza virus (H1N2)miR-206 expressionExperimental influenza infection in pig lung[244]
HIF-1α, and its regulator Four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1)Downregulation of miR-206 and upregulated HIF-1α and Fhl-1 in hypoxic lung tissue and PASMCsmiR-206 targets HIF-1α directly. Hypoxia-induced down-regulation of miR-206 promotes PH in PASMCsHypoxia-induced PH in hypoxic rat model in cultured hypoxic PASMCs[245]
miR-206/NR4A2/NFKB1;NFKB1 stimulates inflammatory cytokines (IL6, IL1B, CCL5)Liposaccharides induce miR-206 expression which targets NR4A2 downregulation, which in turn allows upregulation of NFKB1 activityAstrocyte-associated inflammation during recovery from chronic central nervous system injury[246]
Indirectly: inflammatory cytokines (IL6, IL1B, CCL5)
Cellular factors influencing myomir expression/activity
Skeletal muscle
Positive regulatorNegative regulatorRegulated target miRTissue/cellRef.
Myogenin, MyoDUpregulates miR-1-1 and miR-133a-2Primary human myoblasts; C2C12 cells[11]
Upregulates miR-1-2 and miR-133a-1
SRF, MyoD and MEF2Upregulates miR-1-2Muscle somites[30]
MEF2Upregulates miR-1 and miR-133aSkeletal muscle[9]
KSRP (part of Drosha and Dicer complexes)miR-206 binds 3’-UTR of KSRP and inhibits its expressionKSRP upregulates miR-1 expressionSkeletal muscle[35,37]
RNA-binding protein LIN28LIN28 upregulates miR-1 expression; LIN28 promotes pre-miR-1 uridylation by ZCCHC11 (TUT4)Cardiac muscle of patients with muscular dystrophy[36]
MBNL1MBNL1 downregulates miR-1 expression; MBNL1 binds to UGC motif in the loop of pre-miR-1 and competes for the binding of LIN28; MBNL1 blocks DICER processing of pre-miR-1Cardiac muscle of patients with muscular dystrophy[36]
CX43 and CACNA1C calcium channelCX43 and CACNA1C both increased in both DM1-/DM2-affected hearts, contributing to the cardiac dysfunctionsCX43 and CACNA1C are direct targets of miR-1 repressionCardiac muscle of patients with muscular dystrophy;[36]
CACNA1C and CX43 encode the main calcium- and gap-junction channels in heart
Utrophin AmiR-206 and KSRP are negative regulators of utrophin AOverexpression of miR-206 promotes the upregulation of utrophin A, via the downregulation of KSRPNormal and dystrophic muscle cells;[37]
miR-206 can switch between (1) direct repression of utrophin A expression, and (2) activation of its expression by decreasing KSRP, allowing close regulation
MyostatinDownregulates miR-1, miR-133a, miR-133b, miR-206Mouse (35 d) pectoralis skeletal muscle[29]
SRFDownregulates miRs-133aSkeletal muscle[1,3]
Prmt5 and Prmt4Upregulates myomiR expression during differentiationMouse skeletal muscle[247]
Smooth muscle
Sp-1 transcription factorpERK1/2Upregulates miR-133(a)VSMCs[248]
Brg1Upregulates miR-133 (ChIP complex with SRF)Smooth muscle[249]
Cardiac muscle
GATA4, Nkx2.5, Myocardin, SRFUpregulates miR-1 and miR-133aDifferentiating cardiac muscle[5]
SRF plus MyocardinUpregulates miR-1-1 and miR-1-2Cardiomycetes[30]
CalcineurinDownregulates miR-133aHypertrophic cardiac muscle[203]
miR-206/ miR-133b
Skeletal muscle
Mrf5Upregulates miR-1, miR-206Skeletal muscle[171]
Myogenin, MyoDUpregulates miR-206Primary human myoblasts; C2C12 cells[11]
MyoDUpregulates linc MD1 (encodes miR-133b)Differentiating myoblasts[11, 38]
Binds to (E-box) enhancer of miR-206, miR-133bskeletal muscle (mouse)[12,40]
Upregulates miR-206/miR-133bDifferentiated human foetal skeletal muscle cells[250]
FGF2 allows upregulation of Sp1/Cyclin D1Downregulates p38-mediated miR-1/133 expressionRegenerating rat skeletal muscle[212]
MyostatinDownregulates miR-133a, mir-133b, miR-1, and miR-206Mouse (35 d) pectoralis skeletal muscle[29]
TWEAK downregulates myoD and MEF2cDownregulates miR-1-1 and miR-133Degenerating/wasting skeletal muscle[59]
HMOX1 downregulates MyoD and myogeninDownregulates all myomiRsInflamed skeletal muscle[60]
L-Thyroxine treatmentDownregulation of pri-miR-206 and pri-miR-133bHuman skeletal muscle[230]
No effect on miR-1/miR-133a pairs
Smooth muscle
p-ERKActivated extracellular signal-regulated kinase p-ERK inversely correlated with VSMC growthDownregulates miR-133 expressionVSMCs[248]
Other tissues
MyogeninBinds miR-206 enhancer (ChIP)Fibroblast cell line:[40]
IGF-I signallingUpregulates miR-133bMouse Adipose derived stem cells[71]
L-Thyroxine deficiencyUpregulated Col5a3Strong upregulation of miR-133a and -133bHypothyroid mouse liver[232]
Downregulated Slc17a8, Gp2, Phlda1, Klk1d3, Klk1 and Dmbt1Strong upregulation of miRs -1, -206
Upregulated Vldlr and Akr1c19, and downregulated Upp2, Gdp2, Mup1, Nrp1, and Serpini2
L-Thyroxine treatmentPre-miR-206 and Pre-miR-133b down-regulatedUpregulation of Gdp2 andMup1Hypothyroid mouse liver in vivo, and in vitro mouse hepatocyte AML12 cells[232]
PA2G4, mps1, cdc37, cx43, cldn5; cx43 is a miR-133 targetUpregulation of cell cycle factors mps1, cdc37, and PA2G4, and cell junction components cx43 and cldn5Suppression of miR-133a1 stimulates cardiac cell proliferationRegeneration of damaged Zebrafish cardiac muscle, associated with reduced miR-133a1[167]
FgfUpregulated FgfDownregulates miR-133Zebrafish regenerating fin blastema[67]
SHP (nuclear receptor)Downregulation of miR-206 in nuclear receptor SHP(-/-) miceSHP(-/-) mice strain, mouse liver[251]
AP1 transcription factor complexAP1 induced miR-206 promoter transactivity and expression; this is repressed by YY1ChIP analysis shows physical association of AP1 (c-Jun) and YY1 with miR-206 promoterSHP(-/-) nuclear receptor mice strain, mouse liver[251]
NR3B3YY1 promoter transactivated by ERRgamma; this inhibited by SHP (NROB2)Nuclear receptor ERRgamma (NR3B3) binding site on the YY1 promoterMouse liver[251]
Novel cascade "dual inhibitory" mechanism governing miR-206 gene transcription by SHP(1) SHP inhibition of ERRgamma leads to decreased YY1 expression(2) Derepression of YY1 on AP1 activity, leads to activation of miR-206Mouse liver[251]
Il17a/f locusmiR-133b and miR-206 expressionCoregulated with IL-17 productionαβ and γδ T cells[80]
Figure 2
Figure 2 Alignment of the principal transcripts of the miR-206/miR-133b locus of (A) mouse chromosome 1 and (B) human chromosome 9, compiled from several sources. A: The primary long intergenic non-coding polyadenylated RNA (linc-MD1) of 15 kb is initiated at the upstream distal promoter (DIST) and encompasses both microRNA-206 and -133b genes, however maturation of the pri-linc-MD1 results only in the release of pre-miR-133b which maturates into mir-133b which accumulates in the cell nucleus, as well as the mature 521 bp spliced linc-MD1 RNA which accumulates in the cytoplasm of skeletal muscle cells[38]. The mature linc-MD1 RNA sequence contains binding sites for miR-135 and miR-133 and acts as a complementary “sponge” to regulate their abundance and regulate expression of their target genes including key muscle transcription factors. Accumulation of linc-MD1 RNA and miR-133b are mutually exclusive. The DIST promoter contains E-box sequences recognized by MyoD and is active in differentiating muscle cells when increasing levels of MyoD induce the expression of linc-MD1 or miR-133b. In contrast, the primary transcript of miR-206 initiates at an independent proximal promoter (PROX) which is located intronic to linc-MD1 gene and is already active in undifferentiated proliferating cells. The PROX promoter binds both MyoD and myogenin (ChiP data)[38] and is functional in the presence of myogenin alone, although increased expression activity is also associated with differentiation of muscle cells[11]. The primary expressed transcript for miR-206 is likely coincident with the 5.3 kb random cloned mouse transcript cDNA, GenBank sequence AK132542[40], although the first 13 nt of the pre-mir-206 sequence is absent from that sequence. A second polyadenylated non coding RNA 7H4 was previously identified in rat muscle cells which are specifically associated with nerve synapses[39] and is expressed at rat development stages coincident with the strong expression of MyoD and myogenin[11]. The 5.2 kb long 7H4 ncRNA clone is slightly truncated at the 5’ terminus compared to the AK132542 sequence, and may represent a processed product from which pre-miR-206 has been cleaved[8]. A second 1.6 kb short 7H4 ncRNA transcript, exactly coincident with the 3’ terminal region of the longer transcript, is also abundant in rat muscle[39] and may represent a second processing product; B: The lnc RNA RP11-771D21.2 (Hs.582788) has been identified in RNA seq libraries and aligned with known genomic loci. Information about the regulation of its expression is not available.

Others have noted that the canonical myomiRs act as balanced regulators, often specifying broadly opposing functions. The miRs-1 and -206 are semi-homologous with closely similar mature sequences (and identical seed sequences), and target some genes in common, as well as independent targets. The identical mature seed sequences of miRs-133a and -133b implies they would share many targets in common, yet each of these miRs appear to have distinct cellular functions, with miR-133a expression common to all muscle and miR-133b abundant in all muscle types, except cardiac muscle. Loosely, the cell signalling pathways targeted by miR-1/-206 tend to have opposing functions to the regulatory pathways targeted by miR-133a/-133b. Both miR-1/ -206 act to promote myogenic differentiation, while the miR-133 isomers maintain the undifferentiated state and promote cell growth; hence co-expression of the myomiRs likely aids maintenance of homeostasis under normal cellular conditions.

This difference in expression of the related myomiR members in cardiac muscle compared to skeletal muscle may be associated with the physiological specialization of cardiac muscle, or its greater constancy of fibre type and function. In contrast, skeletal muscles constitute a variety of differentiated fibre types and are more plastic, capable of undergoing marked changes in myofibre content and physiology related to the level of use and workload[1,3]. As understanding of the molecular regulation of muscle types have deepened, it is clear that the physiological and functional specializations are also reflected in the functions of the myomiRs.


Studies with mammalian stem cells reveal broad functions for the myomiRs in the definition of primary differentiation pathways. Both miR-133 and miR-1 have roles in early cell programs leading to differentiation of muscle[2,10,13]. Pluripotent mammalian embryonic stem (ES) cells undertake cell fate decisions controlled by activation and repression of lineage-specific gene sets. These decisions are dictated by signalling networks which progressively narrow and specify the potential of ES cells as differentiation progresses. Muscle specific miR-133(a) and miR-1 both promote mesoderm formation from ES cells and suppress ectoderm and endoderm fates[2], but later during further differentiation into cardiac muscle progenitors, these miRs appear to have opposing regulatory functions[11,13]. Many non-muscle cell genes are repressed by miR-1 and miR-133 during this early ES cell differentiation program, suggesting that these two miRNAs may have general roles to regulate early ES cell-fate decisions from pluripotent cells[13], with miR-1 specifically targeting the translational repression of Dll-1 and Cdk9[10].

In vivo, the deletion of both miR-133a1/2 genes causes lethal cardiac (ventricular-septal) abnormalities in about half of the mouse embryos or neonates, while mice deficient in only one of either miR-133a-1 or -133a-2 have phenotypically normal hearts[14]. Skeletal muscles are normal in both double and single mutant miR-133a mice (dead and surviving), implying that miR-133b can replace the absent miR-133a species in skeletal muscle and continue the regulation of normal development. In double mutant mice lacking all miR-133a, smooth muscle gene expression was activated 2-4 × and cardiomyocytes (but not cardio-fibroblasts) proliferated 2.5 × faster than normal, accompanied by increased expression of miR-133a targets, including PTBP2, CDC42, cell cycle control factors and cyclins D1, D2 and B1[14]. Recently, both adult and neonatal human foreskin fibroblasts were found capable of being reprogrammed towards cardiac muscle by exogenous expression of only several factors, myocardin, HAND2, T-box-5, GATA4, and miR-1, miR-133a and miR-499[15]. These stimulated cells expressed cardiac specific proteins and showed spontaneous contractility, emphasizing the role of these miRs in the control of specific cell development programs via the modulation of specific factor targets. Further, both human and mouse fibroblasts can be reprogrammed to form cardiomyocyte-like cells by overexpression of cardiac transcription factors (Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and Myocd) along with miR-133a, which directly represses Snai1 which normally regulates EMT processes[16]. Interestingly, exogenous miR-133b can also downregulate Snai1 expression, suppressing fibroblast genes and upregulate the expression of a number of characteristic cardiac cell genes in vitro, yet it cannot replace miR-133a during normal heart development in vivo.


Heart contractility and heart rate are stimulated during chronic pressure overload by activation of the sympathetic nervous system causing catecholamine release. The catecholamines activate β-adrenergic receptors and overstimulation is a component of heart disease. MiR-133 directly targets adenylate cyclase VI and the catalytic subunit of PKA, both elements of the β1AR signal transduction cascade, reducing signalling[17]. Similarly carvedilol, an in vivoβ-adrenergic blocker, improves the cardiac function in infarcted rats by restoring miR-133 expression, resulting in reduced cardiomyocyte apoptosis[18]. In vitro overexpression of miR-133a in cardiac cells has similar effects to carvedilol by downregulating caspase-9 and caspase-3 expression in the presence of H2O2. Overexpression of miR-133a also reduces ROS and malondialdehyde content, and increases SOD activity and GPx levels, protecting cardiomyocytes from apoptosis. Studies in mouse by Caré et al[6] also demonstrated that downregulation of both miR-133 and miR-1 are involved in cardiac hypertrophy. Specific targets of miR-133 such as RhoA, Cdc42 and Nelf-A/ WHSC2 can accumulate and contribute to the hypertrophy of cardiac myocytes during infarction.


Liu et al[2,9] (2007, 2010) also established a fundamental model of differential expression of cistronic miR-1 and miR-133a genes during myogenesis and differentiation of skeletal muscle, smooth muscle and cardiac muscle. The factor MEF2 controls expression of the miR-1-2/-133a-1 cistron via at least two MEF2 enhancer loci: one MEF2 enhancer located 3’ upstream of the miR-1-2 gene, a second intragenic MEF2 enhancer located upstream of the miR-133a-1 gene and a third (less defined) locus far upstream that requires MyoD for expression[19]. Transcripts of pri-miR-1-2/-133-a-1 (bi-cistron), pri-miR-1 and pri-miR-133a-1 genes indicate that both proximal enhancers are functional[1]. Others have emphasized the distribution of these regulatory enhancers[2] drawing attention to the differential expression of these cistronic miRs which the regulatory factor binding sites provide. The regulation of expression of the cistronic miRs by these key muscle development regulatory factors, which are themselves targets of repression by these self-same miRs, also emphasizes the precise inter-regulatory control of each of the various developmental program factors.

Notably, the 2,6-disubstituted purine reversine can induce differentiation reversal (de-differentiation) of C2C12 murine myoblast cells back into multipotent progenitor cells[20]. This occurs by inhibition of Aurora A and B protein kinases, reducing histone H3 phosphorylation, which in turn induces chromatin remodelling and restores cell multipotentency. Reversine treatment also stimulates expression of polycomb genes, Phc1 and Ezh2, leading to inhibition of expression of the muscle-specific transcription factors, myogenin, MyoD, and Myf5[21]. Concomitantly, reversine strongly inhibits miR-133a expression in C2C12 cells through the reduced expression of SRF transcription factor and by reduction of its binding to the miR-133a enhancer and by reduced epigenetic histone modifications on the miR-133a promoter, including reduced trimethylation, phosphorylation, and acetylation[22]. The co-overexpression of a miR-133a mimic along with reversine treatment prevents C2C12 myoblast de-differentiation, indicating the central role of the inhibition of miR-133a expression to the de-differentiation process. Significantly, reversine induced de-differentiation of committed cells is not limited to myoblasts, and reversine treatment can transform primary murine dermal fibroblasts into myogenic-competent cells within regenerating muscle in vivo[23].

Skeletal muscle myogenesis also involves the IGF signalling pathway[24], which activates muscle proliferation and differentiation via the PI3K/AKT pathway. The IGF pathway is regulated by miR-133-a1 which directly inhibits translation of IGF-1R protein, resulting in repression of PI3K/AKT pathway activity. IGF-1, which increases and activates IGF-1R during myogenesis by binding and inducing its phosphorylation, also indirectly activates myogenin, which in turn activates miR-133 activity. Thus miR-133 provides a negative regulation loop to monitor and control PI3K/AKT pathway activity. Similarly, miR-1 targets and reduces the activity of IGF-1 in differentiating C2C12 skeletal muscle cells and in heart muscle during cardiac failure states[25], meanwhile active IGF-1 signalling pathway downregulates miR-1 via repression of FoxO3a transcription factor. Thus, miR-1 also mediates the activity of the IGF-1 signal pathway and is itself feed-back regulated by the IGF-1 signal transduction cascade. Significantly, IGF-1 signalling (IGF-1 and IGF-1R) has key roles in the growth and development of many tissues[26], and also in the progression of many cancers (see later).


Skeletal muscles are plastic tissues in which the ratios of muscle fibre type (slow or fast twitch, smooth muscle, etc.) are to some degree responsive to remodelling through environmental input and nerve control. The muscle fibre type is maintained by the type of nerve signals received by the muscle, and transition between fast and slow twitch fibres can occur over time if nerve signals are changed from slow to fast type, and vice versa[27]. Similarly, prolonged workload or exercise can alter muscle fibre type and its metabolism to allow it to better respond before exhaustion. Muscle development programs regulated by miR-1 and miR-133a play important roles in muscle remodelling[4], and in hypertrophic skeletal muscle miR-1 and -133 levels are decreased[28], indicating that functional overload of muscle induces regulatory alterations which are in part influenced via altered miR activities.


Myostatin is a repressor of myogenesis, and its downregulation allows increase of miR-1, -133a, -133b and -206 expression, activating muscle cell proliferation[29]. In contrast, myogenic factors myogenin and MyoD are well known positive regulators of myomiR expression in muscle that bind upstream of miR-1/-133a genes at defined enhancer regions[2,11]. SRF, MyoD and MEF2 are also direct transcriptional activators of myogenesis-related miR-1 expression in cardiac muscle[2,30]. Since downregulation of myostatin permits expression of miR-133b/-206, and MyoD and myogenin also binds the miR-206 promoter[11], suggesting that miR-206/-133b expression in muscle may also be in part controlled by MyoD/ myogenin.

The ERK1/2 signalling pathway also regulates expression of miR-133 during myogenesis in the C2C12 cell model[31], and its activity is also feedback influenced by miR-133. During myogenesis both miR-133a and -133b are upregulated, and both FGFR1 and PP2AC which function in the ERK1/2 pathway signal transduction are negatively regulated post-transcriptionally by both miRs. Inhibition of ERK1/2 pathway signalling inhibits C2C12 cell proliferation, stimulating initiation of differentiation and forming small truncated myotubes. Importantly, ERK1/2 signalling pathway activity negatively regulates expression of miR-133, providing a feedback loop between miR-133 levels and ERK1/2 signalling activity, forming an additional reciprocal mechanism for regulating myogenesis.

Recently other cellular factors have been identified that influence post-transcriptional maturation or bio-availability of myomiRs in muscle. mTOR regulates miR-1 indirectly in regenerating mouse skeletal muscle and differentiating myoblasts[32]. mTOR most likely affects MyoD protein stability, which then alters miR-1 expression through the availability of MyoD to bind its upstream enhancer. A pathway downstream of mTOR also operates in which miR-1 suppression of HDAC4 results in production of follistatin, which subsequently activates myocyte fusion. This suggests that an mTOR-miR-1-HDAC4-follistatin pathway regulates myocyte fusion during myoblast differentiation and in regenerating skeletal muscle.

King et al[33] (2014) demonstrated that the RNA-binding TDP-43 protein interacts with miR-1/-206 family (but not the miR-133 family) in skeletal myoblast cells, limiting their bioavailability by preventing interaction with the RISC silencing complex, noting this is the first observation of a mechanism differentiating between mature bicistronically encoded miRs, which selectively modulates the bioactivity of downstream targets of the sequestered miRs. TDP-43 accumulates in motor neurons during ALS, a neuromuscular wasting disease. Two miR-1/-206 targets, IGF-1 and HDAC-4 are elevated in both ALS-model transgenic mouse muscle and in cells modified to overexpress TDP-43. The authors suggest the decreased miR-1 (-206) activity in ALS affected muscle could alter retrograde signalling at the NMJ through the dysregulation of both HDAC-4 and MEF-2, whereby miR-1 refines synaptic function by coupling changes in muscle activity to changes in presynaptic function[34].

Factors KSRP[35], MBNL1 and RNA binding protein LIN28[36] also positively and negatively regulate miR-1 biogenesis respectively. Additionally, miR-206 binds to 3’-UTR sites of KSRP transcript to inhibit KSRP expression in skeletal muscle[37]. Independently, miR-206 and KSRP are negative regulators of utrophin A, but unexpectedly, overexpression of miR-206 in both normal and dystrophic muscle cells promotes upregulation of utrophin A, via the downregulation of KSRP. Thus, miR-206 appears capable of switching between direct repression of utrophin A expression and the activation of its expression through decreased KSRP, the two molecular mechanisms providing close counter-regulation of utrophin A expression.


Although the microRNA-206 and -133b are thought typical of muscle specific miRs, little is known explicitly of their functions in skeletal muscle. Cesana et al[38] (2011) showed that miR-133b gene transcript in mouse is located within the precursor of the long (spliced) non-coding RNA linc-MD1 which is expressed under the control of an upstream distal (DIST) cistronic promoter[12] (Figure 2A), while the miR-206 gene, which is located within the intron of linc-MD1, is transcribed autonomously under control of its own proximal (PROX) promoter. In proliferating myoblasts, only primary miR-206 transcript is expressed strongly, initiated from the PROX promoter. During mouse muscle differentiation, long distance interactions bring the DIST promoter into conjunction with PROX and the polyA addition regions of linc-MD1, facilitating the co-expression of linc-MD1 RNA, as well as the primary miR-206 transcript, with the PROX promoter activated by both MyoD and myogenin binding[11]. Notably, mature linc-MD1 RNA contains binding sites for miR-133 (and miR-135) acting as a binding “sponge” to downregulate their free abundance, in turn contributing to the expression regulation of the targets of these miRs, which include key muscle transcription factors[38]. In mouse muscle, the expression of mature linc-MD1 RNA mutually excludes the expression of miR-133b, which must be excised from the linc-MD1 pre-transcript. In the rat genome, a distinct ncRNA 7H4, covering less than half of the mouse linc-MD1 precursor transcript, but closely similar to a mouse RNA AK132542 transcript, also encodes the miR-133b gene, suggesting a similar function to linc-MD1 may occur in rat[39].

Figure 2A uses information from Cesana et al[38] (2011) and Rosenberg et al[40] (2006) to illustrate the aligned transcript regions of the mouse pri-linc-MD-1, the 5.3 kb random cloned mouse transcript cDNA (GenBank sequence) AK132542 and the 5.2 kb rat 7H4 ncRNA transcript. The independent pre-miR-206 transcript overlaps almost completely with the AK132542 transcript which is likely the mouse homolog of the expressed rat ncRNA 7H4. The 7H4 RNA gene is almost fully conserved in the mouse genome, with the 7H4 RNA overlapping the 3’ exon of linc-MD1 gene (containing miR-133b gene) almost to the 3’ terminus of the miR-206 gene. Velleca et al[39] (1994) found two major transcripts of 7H4 RNA, a long 5.2 kb molecule, and a short 1.6 kb molecule coincident with the 3’-terminal region of the 5.2 kb transcript. The 1.6 kb fragment is much more abundant than the full length molecule, suggesting it is a product from the excision of miR-133b from the full length primary transcript. Notably, both long and short ncRNA 7H4 transcripts contain the entire miR-133b gene locus, suggesting they may function in rat similar to mature linc-MD1 in mouse, to bind complementary miRNAs, including miR-133. Similarly in man, ncRNA RP11-771D21.2 may represent the functional human homologue of mouse linc-MD1 RNA (Figure 2B).

Recently Legnini et al[41] (2014) reported that the mutually alternative synthesis of linc-MD1 and miR-133b is controlled by the pleiotropic mRNA regulator protein, HuR. In developing skeletal muscle, HuR favors accumulation of mature linc-MD1 by binding to it and repressing cleavage that would release pre-miR-133b. The level of HuR protein expression is also under the repressive negative control by miR-133 targetting, yet the sponging-up of miR-133 by the linc-MD1 helps consolidate HuR expression by forward positive control. Muscle developmental progression to later differentiation stages may involve overcoming this HuR-linMD1 repression of miR-133b expression by the independent miR-133a1/2 isomers which could downregulate HuR expression, allowing miR-133b excision, permitting developing muscle to exit from the control circuit. The level of linc-MD1 correlates inversely with the level of miR-135/-133b, which in turn control the expression of transcription factors MAML1 and MEF2C which are necessary for specific muscle gene expression. Thus, linc-MD1 activity provides another mechanism for pleiotropic regulation, slowing or activating muscle differentiation. Other evidence suggests the influence of HuR on many gene mRNA transcripts depends on the interplay of HuR with particular regulatory miRs that target and control the expression of the self-same mRNAs.

In sum, because the myomiRs target components of key signalling pathways and processes that control muscle cell development and maintenance, expression of the myomiRs is tightly regulated, often via feedback and feedforward circuits that provide both tight regulatory control and the ability to amplify myomiR expression. In muscle the myomiRs display high interconnectedness in terms of the regulation of their expression and the complementary processes that their regulatory functions influence. MyomiR genes are apparently cistronically encoded, yet expression of each of myomiR genes can be individually controlled by various transcription regulatory factors and other interactions such as RNA-RNA binding, such that expression of particular myomiR genes can be selectively enhanced under cellular conditions in which particular transcriptional regulatory factors are available.


MicroRNA miR-206 is expressed (virtually) exclusively in (developing) skeletal muscle[8], contributing to muscle differentiation programs through repression of Idl-3 protein expression, a downregulator of MyoD activity, as well as repressing the p180 subunit of DNA polymerase alpha, essential for DNA synthesis which occurs during differentiation[42]. MyoD itself promotes the expression of the miR-133 cistrons[11]. Further, in fast twitch muscle of mouse[12] and rat[43] miR-206 has been found to promote formation of new neuromuscular junctions following peripheral nerve denervation (scission). The expression of miR-206 and miR-133b are both upregulated strongly in muscle after denervation (as is 7H4 ncRNA), whereas miR-1 and miR-133a are downregulated. Four months after nerve scission, the re-innervated muscle was predominantly type II glycolytic fibres, suggesting that miR-206 may aid the determination of fibre type via down-regulation of MEF2 transcription factor activity[43]. Valdez et al[44] (2014) also examined the role of miR-133b and miR-206 on neuromuscular junction repair in injured mice. In miR-206 null mice, re-innervation was impaired following nerve injury, and in mice null for -133b and -206 genes the same impaired neuromuscular repair was seen as in single gene miR-206 null mice, whilst in single gene miR-133b null mice development and re-innervation proceeds normally following nerve injury. Together, these findings imply that miR-206 is the major regulator of nerve repair and reconnection to muscle following injury. In support, in miR-133b null mice Pitx3 levels were normal and impairment of locomotion was not detectable, controversially implying that miR-133b has no significant roles in neuron development, neuron maintenance and function in vivo[45]. In contrast, other studies with miR-206 null mice show no obvious phenotypic effects, muscles develop normally and mouse physiology appears normal, suggesting that other factors (including miR-133b) can replace miR-206 during development[46]. However, if the miR-206 null mice are then denervated, about 90% of both wt and miR-206 null mice recover and re-innervate after about 8 wk. This strongly suggests that other factors (including miR-133b) can provide redundant functions for the absent miR-206, including promoting compensatory peripheral nerve regeneration. Furthermore, miR-133b directly stimulates neurite outgrowth following nerve damage in rat brain after treatment with multipotent MSC cells[47], suggesting that elevation of levels of muscle miR-133b after muscle denervation is related to nerve regeneration, and that miR-133b may suffice in miR-206 null mice to replace absent functions. These various observations imply the likelihood that both miR-206 and -133b have functions in the recovery and maintenance of nerve-muscle signalling.


Additionally, miR-206 targets BDNF which promotes efficient skeletal muscle regeneration following damage[48]. BDNF also controls the initiation and maintenance of the differentiated state of muscle cells, potentially via the regulation of retrograde signalling at the neuromuscular junction. The loss of neural input to muscle also causes HDAC4 to accumulate, reducing MEF2-regulated gene expression. Importantly, miR-206 targets HDAC4 and fibroblast growth factor signalling pathways in muscle. HDAC4 regulates neuromuscular-related gene expression and acts in the regulation of muscle remodelling, influencing the formation of appropriate nerve types which connect to the muscle[49]. Significantly, it has been shown that expression of miR-1/miR-133a is also regulated by an intragenic MEF2-enhancer[9], and miR-1 also regulates a MEF-2 dependent retrograde signal at the neuromuscular junction, suggesting that members of both myomiR cistons act to maintain neuromuscular homeostasis[34].

In mouse, members of the MyoD muscle transcription factor family, myf-4 and myogenin, are progressively downregulated during maturation from embryonic day 15 to the first postnatal weeks (weeks 1-3), coinciding with induction of muscle innervation[50,51]. In contrast, muscle denervation results in strong expression of MyoD and myogenin, preceding the accumulation of nAChR, α-subunit[39]. Additionally during myogenic differentiation, acetylcholinesterase transcript levels increase dramatically (5 ×), principally due to its stabilization by binding with HuR protein[52], consistent with a regulatory role of HuR in neuron excitability. Normally the expression of MyoD and myogenin is suppressed by activated nerve signal pathways, including by electrical conduction per se, and sets of muscle genes regulated by the MyoD family and myogenin are downregulated by increasing electrical activity and other nerve-derived signals. Thus again, a pronounced neuromuscular maintenance function for miR-206/-133b can be implied from interplay of signalling control between skeletal muscle and nerve. Both myogenin and MyoD induce the expression of miR-133b and -206, while repression of these factors inhibits their expression. On balance it appears that cistronic miR-206 and -133b and linc-MD1 homologues may contribute to programs of regulatory developmental gene expression in growing muscle and peripheral nerve, facilitating programs to interregulate the developing nerve connections with muscle, and speculatively aid in coordinating appropriate nerve and muscle gene expression programs, establishing interactions between skeletal muscles and their appropriate innervating nerves to maintain muscle fibre type and their correct neuromuscular junction associations.


Zhang et al[53] (2014) reported that miR-1 enters skeletal muscle mitochondria efficiently during muscle development whereby it stimulates the translation of specific mitochondrial genome-encoded transcripts, contributing positive regulation to muscle development. This stimulation of translation requires specific base-pairing between miR and its target mtRNA as well as interactions with mt-located Ago2 protein. These observations contrast earlier findings of Das et al[54] (2012) who showed that the mature miR-181c translocates into rat cardiac muscle mitochondria, reducing mitochondrial cytochome oxygenase 1 (mt-COX1) compared to mt-COX2 and mt-COX3 proteins. The reduced mt-COX1 causes mitochondrial complex IV remodelling, resulting in increased mt respiration and increased ROS generation. Recently, Das et al[55] (2014) used cationic nanoparticles to deliver miR-181c into rat cardiac mitochondria in vivo, causing cardiac dysfunction and a tendency to develop heart failure. Taken together, these studies reveal important new miR-mediated regulatory pathways in muscle mitochondria involving direct manipulation of mitochondrial gene expression by cytosolic miRNAs, including by a myomiR.

Importantly in both cardiac and skeletal muscle, mitochondrial UPC2/UCP3 uncoupling proteins regulate energy homeostasis and the rate of development and differentiation, with UPC2 repressing differentiation and promoting cell proliferation. However, MyoD activates miR-133a expression which in turn directly downregulates UCP2 mRNA to alleviate the developmental repression, suggesting a feedback network involving MyoD-miR-133a-UCP2[56]. Additionally, overexpression of myogenin and MyoD in mouse C2C12 myoblasts[57] increase expression strongly from the UCP3 promoter, but act weakly at the UCP2 promoter. Together these observations suggest UCPs helps maintain balance between muscle differentiation and proliferation during myogenesis, regulated by a MyoD-miR-133a-UCP2 feedback network and by differential responsiveness of UCP2 and UCP3 promoters to activation by myogenin and MyoD.

Furthermore, a downregulation of mitochondrial function is associated with skeletal muscle injury, including increased ROS and reduced cellular ATP generation. However, the recovery and regeneration of post-injury skeletal muscle involves the activation and proliferation of resident stem cells, including satellite cells and endothelial precursor cells followed by their differentiation into myocytes. Jash et al[58] (2014) showed during recovery from muscle injury that the AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathways are activated in satellite cells. mTORC1 positively regulated Ccnd1 translation, yet destabilized Ccnd1 mRNA. These opposing effects of mTORC1 were mediated by two miRs which target the 3’-UTR of Ccnd1 mRNA: one being miR-1 which in mTORC-knockdown muscle was downregulated, allowing Ccnd1 mRNA to accumulate. The authors suggest that mTORC may act to coordinate satellite cell proliferation during the activation of myogenesis.


During conditions of skeletal muscle atrophy and wasting, the cytokine TWEAK and its binding receptor Fn14 are elevated, activating catabolic and pro-inflammatory processes[59]. TWEAK inhibits expression of myoD, MEF2C and myogenin which in turn inhibits expression of miR-1, -133, and -206, suppressing differentiation of progenitor cells into myocytes. HMOX1, another factor associated with inflammation[60], also inhibits myoblast differentiation and myotube formation, by inhibition of expression of each of the myomiRs, again by limiting their transcription factors, MyoD and myogenin. Thus, both HMOX1 and TWEAK may be potentially involved in the regulation of broadly common inflammation associated pathways in skeletal muscle.

Interestingly, TWEAK[61] has a role in stimulating the proliferation of normal neonatal rat cardiomyocytes, increasing cell numbers accompanied by expression of cell proliferation markers Cyclin D2 and Ki67, and other cell cycle factors. In contrast, adult rat cardiomyocytes cannot be stimulated by TWEAK because of the developmental downregulation of its receptor Fn14 in adult cells, coincident with the loss of proliferation capacity in mammalian cardiomycetes several weeks after birth. Fn14 is present in neonatal cardiomyocytes, interacting with TWEAK to activate downstream signalling via ERK and PI3K signalling pathways, as well as via inhibiting glycogen synthase kinase-3β.

FAPs are quiescent progenitor cells resident in normal muscle that can facilitate myofibre regeneration after muscle damage by providing factors which stimulate proliferating myogenic progenitor cells. In dystrophic muscle disease, FAPs typically proliferate and give rise to their differentiated progeny, fibroblasts and adipocytes which replace muscle tissue. However, Saccone et al[62] (2014) found in early-stage disease dystrophic (mdx) mouse muscles that HDAC inhibitors can activate and commit FAPs themselves towards regeneration of muscle tissue, by derepressing a “latent” myogenic program. The inhibition of HDAC induces two core components of the myogenic transcriptional machinery, MyoD and BAF60C, which upregulate expression of miR-1-2, miR-133, and miR-206. The structural subunits of the BAF chromatin remodelling complex (BAF60a, BAF60b and BAF60c) bind to Brg1 (the core complex ATPase) and provide functional specificity[63]. BAF60c is a specific member of the complex during myogenesis, and is essential for the myogenesis process. Interestingly, BAF60a and BAF60b are targets for downregulation by miR-133 and miR-1/206, suggesting that such negative regulation increases the availability of (non-target) BAF60c to join the muscle remodelling complex. Furthermore, a recent study of inflammatory myopathies[64] including dermatomyositis, polymyositis, and inclusion body myositis found increased expression of the inflammatory cytokine TNFα was associated with decreased expression of miR-1, miR-133a, and miR-133b in all subtypes, plus the decreased expression of miR-206 in dermatomyositis. TNFα inhibited the expression of myogenic miRNAs in cells in an NF-κB-dependent manner, while the overexpression of miR-1, miR-206, or miR-133a/b could relieve the TNFα blockage of myogenic cell differentiation. Overall, the dysregulation of myomiR expression in muscle degenerative diseases was demonstrated to be intrinsic to the disease progression.

In diseased cardiac tissues, pre-inflammatory reactions involve upregulation of CNN genes, and in vitro the downregulation of CNN2 blocks multiple proinflammatory and profibrotic pathways in mouse activated primary cardiac fibroblasts (PCFBs)[65]. Immune cell chemotaxis towards CCN2-depleted PCFBs is also reduced strongly. CCN2 is a direct regulation target of miR-133b, and silencing of CCN2 expression by siRNA strongly decreases the expression of stretch-induced chemokines, matrix metalloproteinases, extracellular matrix and a cell-to-cell contact protein, indicating that CCN2 is involved in control of multiple signal pathways for muscle regeneration. Exogenous factors also influence muscle recovery after injury. PRP plasma is an enriched source of autologous platelet α-granule-derived growth factors and cytokines which can stimulate tissue healing[66]. When PRP is applied to injured rat soleus muscle, the recruitment, proliferation and differentiation of cells for muscle recovery is stimulated. Molecular analysis showed that 5 d after PRP treatment the expression of proinflammatory cytokines IL-1β, and TGF-β1 was increased strongly, which in turn induced expression of myogenic factors MyoD1, Myf5 and Pax7, and muscle IGF-1Eb isoform, and muscle recovery was strongly accelerated. Concomitantly miR-133a and miR-1 were downregulated (miR-133a markedly), while SRF was upregulated, phosphoryled αB-cristallin was increased, as were apoptotic factors (NF-κB-p65 and caspase 3) which together indicate enhanced cell survival. Overall, PRP contributes to repair of injured skeletal muscle by via the control of secondary pathways (regulated by myomiRs and heat shock proteins) that modulate both inflammatory and myogenic pathways, with each contributing to the regulated tissue regeneration.

Limb regeneration in lower vertebrates

Whilst miR-133 plays a central role is the repair of damaged muscle and nerves in mammals, in lower vertebrates such as amphibians and teleost fish which retain the capacity for regeneration of entire limbs after damage or loss, here the downregulation of miR-133 plays a central role in organizing the reactivation of cells for the repair of complex tissues. Yin and Poss[67] (2008) found that miR-133 controls complex biological processes involving formation of the regeneration blastema, a proliferative mesenchymal cell mass which is the progenitor for regeneration of the lost structures, ultimately developing into organized organs, including connective tissues, muscle, blood vessels and nerve tissues[67]. When zebrafish fins are excised, the depletion of miR-133 is controlled by increased Fgf signalling (Tables 1 and 2). In normal developed fins, high levels of miR-133 are maintained, accompanied by a cessation of Fgf signalling, indicating that high miR-133 levels normally suppresses tissue proliferation factors and signalling pathways, maintaining developed tissue homeostasis[68]. Increased miR-133b also influences spinal cord regeneration in adult zebrafish, reducing the level of RhoA protein, an inhibitor of axonal growth, and stimulating spinal cord regeneration of axons from neurons in particular brain structures[69].

Corneal repair

In mouse cornea after laser ablation injury[70], miR-133b is the most strongly reduced miR (amongst others) during wound recovery, allowing increased expression of its targets which include CTGF growth factor, SMA, and COL1A1. Transforming growth factor β1-treated rabbit corneal fibroblasts also produced significant decrease in miR-133b, associated with significantly increased expression of CTGF, SMA, and COL1A1, and helped to minimise scar development during corneal recovery. See Table 2 for other tissues.


The miR-133b has roles in early stem cell differentiation leading to nerve development. ADSC stem cells can be induced to differentiate into neuron-like cells by IGF-I signalling, which increases miR-133b expression via the downregulation of beta-III-tubulin, Pitx3 and IGF-IR by translational repression of their proteins[71]. Neural differentiation from ADSC involves a feedback control mechanism in which IGF-I upregulates miR-133b, while miR-133b in turn downregulates the signal receptor activity, IGF-IR. Xin et al[47,72] found multipotent MSC cells regulate the growth of neurites via direct exosomal transfer of miR-133b to neural cells. Middle cerebral artery occluded rat brains elevate miR-133b in MSC exosomes, which stimulates neural regeneration. Exosomes transfer to adjacent astrocytes and neurons, reducing the expression of selected miR-133b targets, including CTGF and RhoA[72]. The first identified molecular role for miR-133b was in neural tissue[73] where it regulated the maturation of mammalian midbrain dopaminergic neurons (DNs), along with the paired-like homeodomain transcription factor Pitx3, which itself then regulated the transcription of miR-133b in a feedback control loop.


Several studies found that miR-133 a/b isomers play key roles in the differentiation of brown fat tissues from precursor cells after cold exposure[74-76]. Strong reduction of the transcription regulator MEF2 caused reduction of miR-133a, allowing an increase in the adipocyte progenitor specific Prdm16 (a miR-133 target), which promotes the differentiation of both myogenic precursor cells and white fat precursor cells into brown adipocytes. Adult mouse skeletal muscle satellite cells can differentiate into brown adipose via miRNA-133 targeting of Prdm16, leading researchers to suggest that the presence of these miRs may indicate energy dissipating cell lineages (muscle, nerve), compared to energy storing cells, such as white adipose tissue[76]. Mice with knockdown of miR-133a1/a2 genes respond to cold exposure more strongly than wild-type animals and have increased insulin sensitivity and glucose tolerance associated with activation of the brown fat and thermogenic gene programs in subcutaneous white adipose tissue.


MiR-1 is highly expressed in the hypertrophic zone of growth plate cartilage, some 8-fold higher than in the proliferation zone[77]. MiR-1 strongly promotes chondrocyte proliferation and differentiation, including induction of the expression of chondrocyte markers Indian hedgehog and Col X, and acts by targetting HDAC4. Additionally HDAC4 negatively regulates chondrocyte hypertrophy by inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. In contrast, miR-1 is repressed strongly during hypertrophic (late-stage) differentiation of chondrocytes in growth cartilage[78]. This differentiation could be reversed by transfection and overexpression of miR-1 which repressed the expression of aggrecan, the major cartilaginous proteoglycan gene in human chondrocytic HCS-2/8 cells and normal chicken chondrocytes. Thus miR-1 is a major effector in early growth and cell proliferation, and its repression at late differentiation stages is important for maintaining cartilage integrity.


Several reports of myomiR involvement in specialized immunological processes have recently emerged. Stumpova et al[79] (2014) found that several miRNAs, including miR-133b, were strongly expressed during in vitro maturation of human tolerogenic dendritic cells induced by exogenous IL-10 and TGF-β in comparison to miRs expressed in IL-4-induced and IFN-γ activated dendritic cells. MiR-133b and -206 have been previously reported to be expressed during differentiation of immunocompetent mouse Th17 cells, with miR-133b/-206 cistron transcription occurring along with expression at the nearby Il17a/f gene locus[80]. This feature of T cell differentiation towards an IL-17-producing phenotype is shared between αβ and γδ T cells, where the specific co-regulation of miR-133b and miR-206 with the Il17a/f locus extends to human Th17 cells, suggesting presence of miR-133b/-206 in T cells may be biomarkers for Th17-type immuno-reactions.

Bandyopadhyay et al[81] (2014) examined the effect of overexpression or suppression of miR-133a-1 in differentiated mouse THP1 cells which express the NLRP3 inflammasome, finding that miR-133a-1 overexpression suppresses expression of mitochondrial UCP2, resulting in increased caspase-1 p10 activity which subsequently causes IL-1β p17 cleavage. SiRNA silencing of UCP2 expression enhanced H2O2 stimulated inflammasome activity, and conversely, overexpression of UCP2 decreased the inflammasome activation, suggesting that the mechanism by which miR-133a-1 suppresses inflammasome activation involves the direct targetting of UCP2.

Further, the pulmonary cytokine GM-CSF is normally produced in lung alveolar epithelial cells (AECs) during a defense response. GM-CSF expression is suppressed by oxidative stress via altered mRNA turnover[82], in which miR-133a and -133b are upregulated in primary AECs. In vitro cell experiments confirmed that miR-133a and miR-133b bind the 3’-UTR of GM-CSF and suppress its expression, and that their inhibition can reverse oxygen-induced suppression of GM-CSF expression, suggesting that miR-133 isomers are important regulators of GM-CSF expression in AECs during oxidative stress. Studies of mouse colorectal epithelial cells involving the azoxymethane/dextran sulfate-induced mouse model of colitis-associated cancer found that the induced chronic colorectal epithelial cell inflammation downregulates miR-133a and other miRs associated with the modulation of PI3K/Akt and IGF-1 associated pathways, particularly during the earlier inflammatory stages[83].

Overall, whilst myomiRs miR-1-2, miR-133 and miR-206 have central roles muscle regeneration and (neuromuscular) repair, and in the regulation of aspects of inflammation and immunological responses during regeneration of injured and diseased muscles, miR-133a and miR-133b also appear to be involved in other regulatory processes affecting, repair, inflammation and immunological responses a number of other non-muscle cells/tissues, suggesting that these may involve common signalling pathways in a range of tissues in which myomiR play a regulatory role on the levels of signalling pathway components.


This review also examines the numerous cancers with prominent dysregulation of one or more of the canonical myomiRs, and the molecular events influenced by them. We focus on the deregulated myomiRs and their key target genes (up- or down-regulated) which have demonstrable effects in vitro on cell migration, proliferation or apoptosis, or those which are in vivo risk factors for cancer progression or patient survival. Although cancers characteristically have changed expression of large numbers of different protein genes and numerous different miRs which may contribute to the cancer pathology, these other deregulated genes and factors are not discussed except in relation with the myomiRs or their known targets. Table 3 lists the deregulated myomiRs reported in many different cancers. In addition, Tables 4 and 5 list targets and pathways influenced by downregulated and upregulated myomiRs respectively, and Table 6 lists validated myomiR targets related to enhanced cancer progression.

Table 3 The deregulated expression of the canonical myomiRs in different cancers.
MiR-1MiR-206MiR-133aMiR-133bCancer typeRef.
++Progressive bladder cancer (TCC)[122]
--Bladder cancer (TCC)[93,156]
---Bladder cancer (TCC)[92,144]
----Bladder cancer[127]1
----Bladder cancer[128]1
---Muscle-invasive bladder cancer[92]
-Proliferating breast cancer[108]
-ERα-positive breast cancer[109]
--Breast cancer[95]
+Progressive cervical carcinoma[117,121]
+Colon cancer[116]
-Colon cancer[101]
+/-Liver metastasis compared to primary CRC[118]
--Colon cancer[95]
--Progressive GIST[281]
-Laryngeal SCC cells[113]
++Liver cancer[95]
-Lung cancers: (NSCLC, adenocarcinomas, lung SCC, large cell carcinoma, and bronchoalveolar cell carcinoma)[100]
-High metastasis lung tumors[107]
-Lung SCC tissue; lung-SCC cell lines[115]
--Lung adenocarcinomas; NSCLC cells[99]
--Lung carcinomas[85,115,131]
--Lung cancer[95]
+Multiple myeloma[152]
+Progressive prostate cancer[123]
-(-)-Prostate cancer[102]
--Prostate cancer[95]
--Recurrent prostate cancer compared to non-recurrent cancer[96]
--Hormone-insensitive prostate cancer cells[102]
--Ovarian cancer[95]
--Testicular cancer[95]
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]
Table 5 Targets and pathways influenced by the upregulated myomiRs in different cancers.
Upregulated miR-133b
Activated p-ERK, pAKT1 cause in vitro proliferation of cervical cancer cell lines, and promote in vivo tumorigenesis and metastasisDownregulation of MST2, CDC42, RHOAUpregulated miR-133bHuman cervical carcinoma tissue compared to surrounding normal cervical tissue[121]
Decreased patient survivalUpregulated miR-133bProgression bladder cancer[122]
Androgen receptormiR-133b directly represses CDC2L5, PTPRK, RB1CC1, CPNE3miR-133b directly upregulated by ARHormone-sensitive human prostate cancer (LNCaP) cells stimulated by androgen[123]
Activativated neuroendocrine neoplasia proliferationMutation in von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase gene (VHL)Upregulated miR-133b expression in VHL- deficient pheochromocytomaHuman pheochromocytoma (PCCs) and paraganglioma (PGLs) neuroendocrine neoplasias[318]
Upregulated miR-206
Cell reprogramming factor KLF4KLF4 downregulated in colon cancer tissue, associated with increased miR-206miR-206 strongly upregulated in colon cancer tissuesHuman colon cancer tissue[116]
Upregulated miR-1 and miR-133
Decreased survival of R172 IDH2-mutated subset of CN-AML patients, increases resistance to chemotherapyDistinctive gene and microRNA expression profiles accurately predicted R172 IDH2 mutationsUpregulated expression of miR-1 and miR-133De novo CN-AML patient bone marrow and blood samples[151]
EVI1 increases aggressive cancer growthEVI1 expression upregulated in established patient samplesUpregulated expression of miR-1-2 and miR-133-a-1EVI1 expressing AML subset of patients[120]
ChIP assays show EVI1 binds to miR-1-2 gene promoter directly
CCND2miR-1 and miR-133a were specifically overexpressed in the cases with t(14;16) translocation, correlates with down-regulated CCND2 expressionUpregulated miR-1 and miR-133-aMultiple myeloma[152]
Secreted myomiRs
miRs selectively released into serum (within exosome microparticles)miR-1, miR-133a, and miR-133b selectively releasedHuman breast cancer[319]
Circulating microRNATumor-derived exosomesHuman non-small-cell lung cancer[320]
Table 6 Validated myomiR targets related to cancer progression.
Up regulated cell factorDown regulated cell factorCancer typeRef.
Downregulated myomiRs
Downregulated miR-1
Mediator complex subunit 1 (Med1) and 31 (Med31) upregulatedmiR-1 downregulatedOsteosarcoma[257]
Slug expression upregulated; enhanced cell migratory and invasive activitiesmiR-1 downregulatedChordoma[261]
Slug expression upregulated; stimulation of EMT processmiR-1 reduced increasingly with cancer progressionProstate adenocarcinoma[321]
Downregulated miR-133a
ARPC5 upregulated;Downregulated miR-133a (> miR-206)Lung SCC[115]
CAV1 upregulated;miR-133a downregulatedHNSCC[322]
Moesin upregulated;miR-133a downregulatedHNSCC[143]
FSCN1 upregulated;miR-133a/ miR-133b downregulatedESCC[132]
Bladder cancer (TCC)[274]
GSTP1 upregulated;miR-133a downregulatedHNSCC[323]
Bladder cancer (TCC)[144]
Lung SCC[115]
LASP1 upregulated;miR-133a downregulated in 83% of colorectal tumorsColorectal cancer[136]
CAV1 downregulated with miR-133a levels, and is lowest in metastatic cancers;Contrastingly, higher levels of miR-133a correlate with poor prognosis and increased metastasis
FSCN1 upregulated in non-metastatic tumors
LASP1 upregulated;miR-133a downregulatedBladder cancer (TCC)[313]
PKM2 upregulated;miR-133a downregulatedTSCC[111]
Moesin upregulated;miR-133a downregulatedHNSCC[143]
EGFR upregulated;miR-133 downregulatedHormone-sensitive prostate cancer cell lines[324]
Human TERT telomerase catalytic subunit upregulated;miR-133a downregulated[325]
TCF7 transcription factor upregulated;miR-133a downregulated[325]
FSCN1 and MMP14 upregulated;miR-133a downregulatedESCC[326]
Reduced miR-133a expression correlated significantly with advanced clinical stages, poor histological differentiation and lymph node metastasisMarked downregulation of miR-133a in primary EOC tumors and OVCAR-3 cell lineEpithelial ovarian cancer (EOC), and in OVCAR-3 cell line[327]
Downregulated miR-133b
FSCN1 upregulated;miR-133a/-133b downregulatedESCC[132]
FSCN1 mRNA upregulated;miR-133b downregulatedProgressive GIST[281]
BCL2L2 upregulated;miR-133b downregulatedLung cancer[85]
MCL1 upregulated;miR-133b downregulatedLung cancer[85]
MET upregulated;miR-133b downregulatedColorectal cancer[87]
MET protein upregulated;miR-133b downregulatedhigh grade osteosarcoma tumor samples and cell lines[328]
EGFR upregulated;miR-133b downregulatedNSCLC[105]
Multiple cell factors elevated;miR-133b downregulatedProstate cancer[282]
FGFR1 downregulated;miR-133b downregulatedGastric cancer[329]
Gli1 protein downregulated by miR133b, Gli1 target genes, OPN and Zeb2, are indirectly regulatedmiR-133b downregulatedGastric cancer[283]
TAp63 supresses metastasis; downregulation target of miR-133bmiR-133b is a transcription target of TAp63, downregulatedColon cancer cells[330]
Chemokine (C-X-C motif) receptor 4 protein downregulated by miR133b; upregulated in advanced cancermiR-133b downregulatedCRC[331]
TBP-like 1 mRNA and protein are upregulated in CRCmiR-133b downregulated in CRCCRC[332]
Strong additional down regulation of miR-133b aids liver metastatic niche for CRC cellsmiR-133b downregulated 3 × (significant) in liver metastasis compared to primary CRCmiR-133b downregulated in primary CRC compared to surrounding tissueMetastatic cancer arising from primary hCRC[333]
Interestingly, miR-133b is not downregulated significantly in lung metastasis compared to primary CRC
SP1 targeted directly by miR-133, causing reduced expression of MMP-9 and Cyclin D1miR-133a and -133b downregulatedGastric cancer[334]
miR-133b target MMP-9 is upregulatedmiR-133b downregulatedRCC[335]
Downregulated miR-206
ERαERα downregulates miR-206ERα-positive breast cancer;[294]
miR-206 downregulatedDouble feedback loop[109]
miR-206 downregulated[293,336]
ERαmiR-206 downregulatedEEC tissue[110]
SRC-1, SRC-3 and GATA-3 proteins contribute to estrogenic signallingmiR-206 downregulatedERα-positive breast cancer[296]
Signalling contributes to Luminal-A phenotype
KLF4 over expressed in proliferating cells and cancers.miR-206 levels are KLF4 dependent. KLF4 and miR-206 feedback pathway oppositely affect KLF4 protein translationBreast cancer cells and normal cells[108]
FGBP1miR-206 gene double knockdownmiR-206-/- mouse skeletal muscle.[12]
VEGF upregulatedmiR-206 downregulatedLaryngeal SCC cells[113]
VEGF upregulatedmiR-206 downregulatedCRC tumors compared to matched normal tissue; (1DS assay)[337]
miR-206 correlates with negative ER status, negative PR status, and negative HER-2 statusDownregulated miR-206Breast cancer tumor tissue[338]
miR-206 was downregulated in clinical TNBC tumor samples, one of its targets, actin-binding protein coronin was upregulatedDownregulated miR-206 associates with increased metastasis potential in breast cancersHigh metastatic capacity TNBC tumors[305]
Downregulated miR-1 and miR-133a
PNP upregulatedmiR-1/miR-133a downregulatedMSSCC[137]
Prostate cancer[97]
Bladder cancer (TCC)[312]
TAGLN2 upregulated;miR-1/miR-133a downregulatedMSSCC;[137]
Bladder cancer (TCC)[93]
PTMA upregulatedmiR-1 and miR-133a downregulatedBladder cancer (TCC)[312]
Downregulated miR-1 and miR-206
MET levels correlated inversely with miR-1/206 expressionmiR-1/206 downregulatedUp-regulation of MET in rhabdomyosarcoma[89,288]
HGFR upregulatedmiR-1/206 downregulatedBreast cancer cells[289]
G6PD; PGD; TKT; GPD2 upregulatedmiR-1/206 downregulatedPrimary lung adenocarcinoma[99]
Upregulated myomiRs
Upregulated miR-133b
miR-133bmiR-133b strongly upregulatedMST1, CDC42, RHOA, and DUSP1 downregulatedCervical carcinoma[121]
miR-133bmiR-133b is directly upregulated by ARmiR-133b represses CDC2L5, PTPRK, RB1CC1, and CPNE3PCa prostate cancer cell line[123]
Upregulated miR-206
miR-206Strongly upregulated miR-206KLF4 downregulatedHuman colon cancer tissue[116]
Upregulated miR-1 and miR-133a
miR-1-2 and miR-133-a-1Upregulated miR-1-2 and miR-133-a-1EVI1 (transcriptional activator of miR-1 and miR-133b)AML[120,151]
miR-1 and miR-133-aUpregulated miR-1 and miR-133-aDownregulated CCND2Multiple myeloma[152]
Up-regulation of exogenous myomiR expression in cell lines
Reduced cell proliferationEstrogen receptor alphaOverexpression of miR-206 has an inhibitory effect on cell proliferationERα-positive breast cancer cells over expressing mir-206[289]
miR-133bGSTP1 downregulatedTransgenic miR-133b overexpressionHeLa cervical cancer cells[282]
miR-133bFAIM downregulatedTransgenic miR-133b overexpressionHeLa cervical cancer cells[282]
Apoptosis increasedTNFα-induced cell death is activatedTransgenic miR-133b overexpressionHeLa cervical cancer cells[282]
Increased cell proliferation and migrationDownregulation of MST2Transgenic miR-133b overexpressionCaSki cervical cancer cells[121]
Downregulation of CDC42
Downregulation of RHOA
Increased cell proliferation and migrationIndirect upregulation of p-AKT1 activityTransgenic miR-133b overexpressionCaSki cervical cancer cells[121]
Indirect upregulation of p-ERK activity
RB1CC1 downregulatedExogenous upregulation of miR-133b;miR-133bm promotes cell apoptosis, but suppressed cell proliferation and cell-cycle progression in aggressive PC-3 cellsPC3 prostate cancer cell line[106]
miR-133b directly targets RB1CC1 in LNCaP cellsIn contrast in low-aggression LNCaP cells, miR-133b stimulate cell proliferation and cell-cycle progression, but inhibit apoptosisHormone sensitive prostate cancer LNCaP cell line
Cell proliferation decreased and apoptosis increasedMet, Twf1 and Ets1 and Bag4 activities downregulatedmiR-1 expression is lower in mouse cSCCs compared to normal skinMouse cutaneous squamous cell carcinomas (cSCCs); A5 and B9 cSCCcell lines[256]
Transgenic miR-1 overexpression
Ets1 proto-oncogeneRepression of Ets1 expression inhibited HepG2 cell invasion and migrationTransgenic miR-1 overexpressionHCC HepG2 cells[340]
lncRNA UCA1Knockdown of lnc UCA1 expression phenocopied the effects of upregulation of hsa-miR-1hsa-miR-1 decreased the expression of lnc UCA1 in bladder cancer cells in an Ago2-slicer-dependent mannerHuman bladder cancer (TCC) cells[156]
NOTCH3 signallingmiR-206 had a direct inhibition of NOTCH3 signalling and indirect interaction with other signalling pathways via CDH2 and MMP-9miR-206 upregulation blocks the cell cycle, inhibits cancer cell proliferation and migration and activates cell apoptosisSW480 (plus its metastatic strain) and SW620 colon cancer cell lines[341]
FSCN1miR-133b targets FSCN1 in GC cells; the direct knockdown of FSCN1 can also inhibit GC cell growth and invasionUp regulation of miR-133b in GC cells inhibits cell proliferation, cell migration and invasionmiR-133b is significantly downregulated in GC tissues compared with adjacent normal tissues, as well as in GC cell lines[342]
FSCN1miR-133a targets FSCN1 in CRC cells;Up regulation of miR-133a expression and downregulation of FSCN1 protein expression both suppress colorectal cancer cell invasionmiR-133a is significantly downregulated in some colorectal cancer cell lines, as well as in colorectal cancer tissues compared with the normal adjacent tissues[343]
Overexpression of FSCN1 can reverse the inhibitory effect of miR-133a upregulation, reactivating CRC cell invasion

An excellent review by Nohata et al[84] (2012) reported changes in the expression of the miR-1/-133a and miR-206/-133b cistron clusters in numerous cancers, typically finding reduced expression of different combinations of myomiRs, such as in lung cancer[85], colorectal cancer[86,87], rhabdomyosarcoma[88,89], chordoma[90] osteosarcoma[91], muscle-invasive bladder cancer[92], bladder cancer (transitional cell carcinoma) (TCC)[93], ESCC[94], breast cancer[95] and prostate cancer[95-97]. In different cancers (Figure 3) deregulation typically involves downregulation of one or more myomiR isomers, indicating they normally function as tumor suppressors in the tissues, limiting the abundance of factors involved in aspects of cell proliferation[84].

Figure 3
Figure 3 Roles of the myomiRs during cancer progression. Altered expression of myomiRs is associated with cancer progression and metastasis. Note that the changed level of myomiR typically contributes to cancer progression. Reduced levels of a single myomiR are associated with PDAC[103], NSCLC[105] and HCC[98], whilst an elevated single miR is associated with cervical carcinoma[121] and bladder cancer (TCC)[122]. Increased expression of miR-1/-133a is associated with t(14;16) translocation multiple myeloma[152], whilst reduced expression is associated with prostate cancer[102] and RCC[138], respectively. Reduced expression of other myomiR combinations is also associated with TSCC[111], ESCC[132], HNSCC[114,143], GIST[281], bladder cancer (TCC)[93], lung cancer[85,99], colorectal cancer[86,87] and rhabdomyosarcoma[88].

Some cancers however show that elevation of myomiR levels promotes cancer progression (Figure 3), indicating that in such cell environments the deregulated myomiR is oncogenic and their targets here are normal tumor-suppressor cell factors. These are both regulatory roles that myomiRs normally exert, either by influencing particular cell signalling pathways that maintain a differentiated non-proliferating state in mature cell development stages, or by influencing other signalling pathways involved in cell proliferation and tissue genesis stages. Notably, the reports of deregulated myomiRs in cancers often reveal significant relation between the myomiR concentration and tumor severity, with greatest disregulation of expression statistically associated with metastasis, or with tumors of high metastatic potential, or with decreasing prospects of patient survival[88,98-102]. Yet, double knockout mice lacking both miR-133a1/2 gene alleles[14] do not display an elevated incidence of tumors in any organs or tissues in vivo, similarly animals with knockout of miR-206 expression[46], or knockdown of miR-133b or double knockdown of -133b/-206[44] are not reported to be associated with tumors, indicating that the singular lack of myomiR(s) alone is not (usually) sufficient to initiate tumorigenesis. Hence the oncogenic role of the deregulated myomiRs is a significant potentiating one, dysregulating cell signalling pathways in concert with the multiplicity of other molecular and cell environmental changes occurring in the developing tumor.

It is also notable that expression of cistronic myomiR isomers is not co-ordinated in different carcinomas, emphasizing individual deregulation of control of expression of each myomiR gene. For example, at least one miR of either cistronic pair is expressed in 16/20 cancers having altered miR-133 expression, showing also that each miRs has independent expression in non-muscle cells and tissues. Since the myomiRs influence numerous developmental pathways in normal muscle and other tissues, the differential expression of the myomiR isomers may potentially influence the pathology of cancers differently.

Cancer and downregulated myomiRs

Reduced expression of myomiRs was associated with numerous cancers, such as with PDAC[103] colorectal cancer[86,104], NSCLC[105], HCC[98], prostate cancer[102,106], metastatic lung tumors[107], proliferating breast cancer[108], ERα-positive breast cancer[109], EEC[110], NSCLC[85], TSCC[111,112], laryngeal SCC[113], and HNSCC[114] (Table 3). Many of the reports identify reduction in a single myomiR, but in case studies of particular cancers often the different myomiRs have been identified as downregulated, for example in NSCLC tumor samples, miR-1[100], -133a[85,115], -133b[85,115], -206[107] or miR-1/-206[99] have been reported, by implication dysregulation of all of the myomiRs. Similarly, for colorectal cancer, downregulated miR-1[101], -133a[104], or -133b[86], or upregulated miR-206[116], while in prostate cancer downregulated miR-1[101,102] and miR-206[102], miR-133a[97,102] and miR-133b[95,96] have been variously reported (Table 3). Either these studies have examined different subclasses of the particular cancer which have different myomiR profiles, or more likely the method of miR detection or the purpose of the study (e.g., relating a particular miR to a particular deregulated target gene) may have influenced the findings reported, leading to some potentially conflicting and inconsistent reports. Additionally, the mature miR isomers are difficult to distinguish by molecular assay and some reports note cross-identification of miR-133b by Taqman mature miR-133a specific probe[14], which is used in many studies. Others[114,117] also make this point, that the different miR assay platforms generate different profiles which may obscure or confuse the identity of observed molecular changes, and at minimum generate apparently different miR profiles of the same tissues or diseases[118,119].

It is essential to accurately determine the specific expression of particular myomiR isomers and their alleles to understand the control processes of particular pathological states. The expressed alleles of the myomiRs can be assessed accurately by employing pri- or pre-miR RT-PCR assays. For example, only cistron miR-1-2/-133a1 is found expressed in AML, presumably due to specific activation of that cistron[120] and amongst the myomiRs only pre-miR-133b is elevated in cervical cancer[121], in bladder cancer[122], and in progressive prostate cancer[123]. We suggest that initial microarray profiling be confirmed by pri- or pre-miRNA assay of each miR isomer independently.

Significantly, a deep sequencing profile of miR expression in mouse heart[124] found that miR-133b is expressed at about 1/6 of the level of miR-133a, reflecting that microarray-based studies may underestimate the relative levels of important miR isomers. Importantly, such deep sequencing analyses also question the canonical view that miR-133b is not expressed in cardiac tissue, reinforcing the need to employ sensitive and accurate analysis to extend our understanding of miR involvement in biological processes. Discrepancies in miR profiles detected between deep sequencing analysis of liver cancer[344] and microarray/Taqman expression profiling[95], and in comparison of level 3 expression data from the Cancer Genome Atlas (TCGA) with deep sequence data from ovarian cancer patients[119] which found only 1 out of 12 survival-associated miRs identified by sequencing correlated by the TCGA data, emphasize the need for robust analytical and computational methods for in-depth profiling of tumors. Expression profiling of prostate tumors from individual patients by deep sequencing revealed that the expression of numerous miRs changed according to tumor stage[125]; however qRT-PCR of individual miRs at each tumor stage could not consistently confirm these alterations. A detailed survey of miRs using qRT-PCR accompanied by in situ hybridization to confirm the identity of the changed miR expression in matched prostate tumor tissue found less than 50% identity between major altered species when compared with deep sequencing analysis of pooled tumors by the same authors[126]. Furthermore, a deep sequencing profile of expressed miRs in bladder cancer[127] also showed that individual patient profiles varied greatly, and remarkably found also that the majority of deregulated miRs are upregulated in tumor tissue compared to matched normal tissue, with up to 3-5 × more upregulated than downregulated species in some patient tumor samples. Generally however, the myomiRs expressed in normal tissue are found downregulated in tumors when analysed by both qRT-PCR and by sequencing platforms. Significantly, another deep sequencing profile of expressed miRs in bladder cancer[128] revealed a different myomiR expression profile to the above deep sequencing study[127], yet confirmed the pattern of myomiR expression detected previously by the same group using microarray and qRT-PCR techniques[93] (Table 3). Overall, these various platform comparisons suggest the need to re-evaluate the genome-wide miR expression profiles of different cancers by use of deep sequencing and then to confirm findings using independent molecular methods.

Cell factors deregulated in cancer by myomiRs

Teicher[129] (2012) and Frith et al[130] (2013) noted in sarcoma tumors, which arise in diverse tissues of mesenchymal origin, that the upregulation of cMET (MET), HIF-1α, IGFR-1 or EGFR, CDK4, MCL1 or mTOR is observed with some elevated frequency in (particular) sarcomas, related to increased cancer severity and enhanced tumor progression, with the significance of each altered pathway likely due to the differentiated tissue in which the sarcoma arises. Downregulated expression of myomiRs occurs in both some sarcomas and carcinomas, linked specifically to the upregulated expression of some of the above gene targets. The different deregulated myomiRs modulate the levels of numerous mRNA/gene targets, but often particular deregulated gene targets are seen in several different cancers. For example, MET is upregulated due to reduced miR-1 levels in colon cancer[87,101], NSCLC[100] and rhabdomyosarcoma[89]. MET binds specifically with HGF, resulting in activation of pathways causing malignant progression via increased cell mobility, tissue invasion, and reduction of apoptosis. Reduced miR-1 targetting is only one of several cell alterations which can contribute to MET activation, yet the downregulation of miR-1 relates significantly to increased cancer severity, indicating the likely importance of miR-1 as a pleiotropic suppressor of several pathways important for tumor development.

Oncogenic membrane receptors, such as IGFR-1 and EGFR are upregulated in association with reduced miR-133 expression in NSCLC[131], and a similar EGFR upregulation occurs in hormone-sensitive prostate cancer and in breast cancer (Tables 4-6). Furthermore, a marked upregulation of cyclin C, cyclin D1 and CDK4 is seen in skin melanoma tissues associated with the reduced expression miR-206; whilst the BCL2 family of pro-survival molecules (Mcl-1 and BCL2L2) are both strongly upregulated due to a marked decrease in miR-133b levels (> 20-fold) in lung carcinoma tissue[85]. In addition, a detailed investigation of the role of myomiRs in prostate cancer[102] found that miR-1, miR-133a (and miR-206) were epigenetically supressed through promotor modification in numerous tumor samples and in prostate cancer cell lines. In vitro studies with prostate cancer cells showed that the downregulation of miR-1 allowed overexpression of multiple target genes that regulate key pathways affecting cell proliferation and cell migration, such as the actin filament network (FN1, LASP1, XPO6, CLCN3, G6PD), cell cycle and DNA damage control (BRCA1, CHEK1, MCM7) and histone acetylation (HDAC4); and with further downregulation of miR-1 the activation of oncogenic genes such as NOTCH3 and PTMA. Cell studies also showed that miR-206 has similar effects on prostate cancer cell biology as miR-1, suggesting that the combined downregulation of the myomiRs contributes significantly to prostate cancer progression.

In addition, FSCN1 expression is elevated in progressive metastatic ESCC, in breast cancer and in high-grade GIST, in part due to the loss of miR-133 expression[132]. FSCN1 is an actin-binding protein critical to cell adhesion, cell motility, and cell-cell interactions. In normal prenatal pig skeletal muscle, FSCN1 expression increases during major muscle developmental spurts, but postnatally it is expressed highly only in brain tissues during accelerated neural cell development[133]. The CREB pathway is often activated in different metastatic human cancers, causing the upregulation of FSCN1 expression[134]. In HNSCC patients, expression of RSK2 and FSCN1 proteins correlate closely. RSK2 protein expression potentiates filopodia formation and cell bundling, increasing cell invasiveness. Overexpression of FSCN1 can rescue the invasion phenotypes in RSK2 knockdown cells, linking RSK2-CREB signalling to the upregulation of FSCN1. In the highly metastatic PDAC[135], relative FSCN1 expression correlates with expressed HIF-1α levels, suggesting the hypoxic tumor microenvironment might induce FSCN1 expression, contributing to invasion and metastasis. Taken together, the downregulation of the myomiRs can contribute to the deregulated overexpression of oncogenic cell factors such as FSCN1, TAGLN2, KLF4, MET (cMET), IGFR and others, each of which can potentiate dysregulation of other cell signalling pathways, enhancing oncogenesis and metastasis (Tables 4-6).

Interestingly, the oncogenic membrane receptors, IGF-1R, TGFBR1 and EGFR are upregulated in NSCLCs due to the downregulation of miR-133a, whilst NSCLC patients with highly expressed levels of miR-133a tend to survive longer[131] presumably because these target oncogenic proteins are less strongly expressed. In contrast, although downregulation of miR-133a occurs generally in colorectal tumors, tumors with higher miR-133a levels are associated with increased metastasis, adverse clinical characteristics and poor prognosis[136], suggesting that other cell factors contribute to these differences in outcome. Expression of other targets of miR-133a: LASP1, CAV1, and FSCN1 are also deregulated in a complex pattern. While LASP1 showed negative correlation with miR-133a levels, CAV1 instead had significant positive correlation, which increased in patients with distant metastases, while negative correlation of FSCN1 was only seen in non-metastatic patients. Again the relationship between the deregulated myomiR and its deregulated target(s) display a complexity which suggests the involvement of other factors in early developing and metastatic cancer stages.

The upregulation of yet other cell factors were seen with reduced myomiR expression, such as TAGLN2 with the downregulation of miR-1 and -133a in MSSCC[137], in RCC[138], and in CRC, liver cancer and in bladder cancer (TCC) (Table 6). Interestingly, TAGLN2 is a known tumor suppressor, yet its upregulated expression is associated with increased metastasis, and worse patient prognosis. This outcome may be related to findings in HCC where phosphorylation of TAGLN2 by PFTK1 (an oncogenic serine/threonine protein kinase) inactivates its actin-binding function, abrogating its suppression of cell motility[139]. Furthermore, in mouse metaphase I oocytes after IGF-1 treatment, miRNA-133b was upregulated more than 30-fold and target TAGLN2 was downregulated, stimulating growth and maturation of the oocytes[140]. These several reports indicate that both the miR-133 isomers may target TAGLN2.


The (semi-) homologous miRs-1 and -206 are downregulated in many cancers, acting as tumor suppressors (Table 3). The homologues share many of the same oncogenic targets, which may be released from negative regulation in tumors. Recently, Singh et al[99] (2013) demonstrated that downregulation of miR-1/-206 in lung adenocarcinomas (and NSCLC) have major effects on carbon flux and the activity of metabolic pathways associated with cell proliferation and growth. The inhibition of miR-1/-206 expression results (indirectly) from elevated NRF2 which in turn increases the activity of redox-sensitive HDAC4, affecting myomiR expression. Importantly, key targets of miR-1-2 and -206 include enzymes of the pentose phosphate pathway (including G6PD, PGD and TKT) and the tricarboxylic acid cycle enzyme GPD2, which increase their activities and potentiate cancer cell proliferation and compromise patient survival. Pleiotropic factors, such as KLF4, HDAC4 and IGFR-1 are also elevated in gastric carcinoma and in breast cancer cells in part due to the loss of miR-206[108], yet in contrast KLF4 is reduced in colon cancer tissue due to strong upregulation of -206[116]. KLF4 is a zinc-finger transcription factor that binds to the TGF-β1 promoter and is important during normal cellular differentiation and proliferation. KLF4 is highly expressed in normal cardiac fibroblasts where it promotes the formation of myofibroblasts[141].

Some common molecular targets of the isoforms of miR-133 are elevated in different cancers (Tables 4 and 5). Moesin, a member of the ezrin-radixin-moesin protein family which links functionally between the plasma membrane and the actin-based cytoskeleton of cells and is found in invadopodia of metastatic cells[142], is deregulated in HNSCC, breast cancer, CRC, and prostate cancer. In HNSCC cells both miR-133a/-133b target moesin specifically, and restoration of miR-133b levels in HNSCC cells, as well as in PC10 and H157 lung SCC cell lines, reduces moesin expression, inhibits cell proliferation, cell migration and invasion[143]. The phenotype is also associated with elevation of other miR-133 targets such as ARPC5 and GSTP1[115]. Both ARPC5 and GSTP1 levels are elevated in lung-SCC and elevated GSTP1 is seen in bladder cancer (TCC) associated with reduced levels of miR-133a[144].

Several large cohort studies have examined the changes in expressed miR networks in a variety of cancers. Navon et al[95], Hart et al[125], Han et al[127], Itesako et al[128] and Volinia et al[145] noted that the downregulated expression of the miR-133/-1/-206 genes is associated with a variety of solid tissue cancers, with numerous other miRs also having highly significant oncogenic roles in particular cancer types. In sum, the downregulation of the various myomiRs contributes significantly to the upregulation of oncogenic proteins linked to regulation of cell cycle progression in solid tumors, sarcomas and carcinomas.


In yet other cancers in which the upregulation of a myomiR is associated with worsening metastasis or potentiation of cancer severity, the downregulation of different tumor-suppressor factors appears to be critical. In cervical cancer the upregulation of miR-133b is associated with downregulation of Mst2 protein kinase (STE20), Cdc42 and RhoA, which in turn lead to increased p-ERK and pAKT1 signalling activity, resulting in tumorigenesis and metastatic cancer proliferation[121]. RhoA, Cdc42 and other small Rho GTPases are components the Rho-kinase pathway which is a key controller of fundamental cellular processes such as cell motility, cell proliferation, cell division, cell differentiation, cell apoptosis, as well as morphological structure development, epithelial and skin morphogenesis, nerve system and limb development[146-148]. The downregulation of these key factors restricts cell apoptosis, favouring tumorigenesis. Interestingly, elevated levels of RhoA, Cdc42, Nelf-A/WHSC2 are also observed in hypertrophic cardiac muscle, associated with reduced levels of miR-133a[6], suggesting that both isomers of miR-133 may normally regulate these factors (in muscle). Similarly, the disruption of the Mst2 pathway is also associated with the disruption of cell apoptosis, of abrogating cell cycle regulation and with increased tumorigenesis in mouse intestinal epithelium[149], specifically by derepressing the accumulation of Yes-associated protein[150] which results in strong activation of β-catenin and Notch signalling. Elevation of Notch has also been seen in colorectal tumors associated with reduced miR-1 levels.

In AML the levels of expression of both miR-133a and miR-1 were elevated significantly[120,151]; similar to multiple myeloma where upregulation of these myomiRs was associated with the downregulation of the cyclin CCND2[152]. Wang et al[153] (2007) also found in patients with AML that downregulated CCND2 and CCND3 results in dephosphorylation of phospho-retinoblastoma protein and induction of G(1) cell-cycle arrest. These findings suggest that CCND2 may also be downregulated in AML in association with the upregulation of miR-133a and miR-1 levels, similar to multiple myeloma. During development or regeneration of normal muscle, the downregulation of CCND2 strongly enhances the myogenic terminal differentiation of muscle progenitor cells[154]. Taken together, the upregulation of these myomiRs in particular cancers can contribute to the deregulated repression of cell factors such MST2, RHOA, CDC42, CCND2 and others, which then also contribute to dysregulation of other cell signalling pathways, potentiating oncogenesis and metastasis. In contrast, a study of the miR network associated with altered mRNA profiles in AML[155] found that miRs other than myomiRs had highly significant roles in key deregulated pathways. Overall, the several studies suggest that myomiRs also contribute to development of AML.


Long non-coding RNAs (lncRNAs) are emerging as important new regulators of oncogenic pathways in cancers, and miRs are emerging as important regulators of lncRNA activities. Recently Wang et al[156] (2014) reported that deregulated expression of lncRNA UCA1, an important new oncogene in human bladder cancer (TCC), can be downregulated by miR-1 in vitro. These two factors are inversely expressed in bladder cancer tissue in vivo. lncRNA UCA1 expression is induced by HIF-1α which stimulates bladder cancer cell proliferation, migration, and invasion under hypoxic growth conditions[157]. It is also induced by the transcription factor CCAAT/enhancer binding protein α[158], and in another route for potentiation of bladder cancer cell growth and reduction of cell apoptosis the transcription factor Ets-2 binds directly at the UCA1 promoter, stimulating UCA1 promoter activity[159]. In bladder cancer cell lines the transgenic alteration of lncRNA UCA1 levels positively influences AKT expression and activity, and cell cycle progression could be reduced by inhibition of the PI3-K pathway, indicating that lncRNA UCA1 affected cell cycle progression through CREB[160]. Taken together, lncRNA UCA1 regulates the cell cycle through CREB and via PI3K-AKT-dependent pathways in bladder cancer. Interestingly, several of the cellular factors which are induced by lncRNA UCA1 are also regulated at the expression level by myomiRs. miR-206 targets HIF-1α directly, hence hypoxia-induced downregulation of miR-206 promotes pulmonary hypertension via elevated HIF-1α in hypoxic rat model pulmonary artery smooth muscle cells (Table 6). Additionally, during regeneration of injured muscle, the AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathways are activated in satellite cells, which involve regulation by miR-1[58]. The involvement of myomiRs in the regulation of these cellular factors in muscle cells suggests a potential for involvement of lncRNA UCA1 in the regulation of normal cellular processes involving the above protein factors.

Recently, the lncRNA MALAT1 which is upregulated during the differentiation of myoblasts into myotubes in normal muscle biogenesis[161] was also reported to be upregulated in several non-muscle cancers associated with worsening patient outcomes[162,163]. In skeletal muscle MALAT1 expression is downregulated by myostatin[161], whilst the silencing of MALAT1 expression in the mouse myoblast C2C12 cells results in the reduction of SRF transcription factor at both RNA and protein levels as well as reduced myocyte differentiation[164]. The MALAT1 transcript has a functional miR-133 target site, thus miR-133 acts as a competing endogenous RNA, regulating MALAT1 levels, which in turn modulates SRF activity. SRF also regulates the expression of miR-133a in C2C12 cells by its binding to the miR-133a enhancer[22], indicating a complex regulatory loop involving SRF, miR-133 and MALAT1.


Considering the central role of the myomiRs in the cell biology of myogenesis and muscle cell differentiation, in muscle metabolism, as well as in muscle remodelling and recovery from injury, it may be expected that they regulate the expression of numerous other target genes, in addition to the well documented pathway genes associated with key processes. In non-muscle-tissue cancers in which myomiRs play critical roles, the myomiRs influence expression of a variety of intermediary regulatory pathway genes, causing the potentiation of tumour development and metastasis. Literature searches (PubMed) show that essentially all myomiR targetted genes detected in different cancers have identified roles in several aspects of muscle cell biology. Thus, the myomiRs likely influence the expression of these gene targets in muscle in a normal regulatory manner, yet in non-muscle cancers the deregulated expression of myomiRs contributes to the dysregulated expression of these various gene targets, to the advancement of cancer development.


This review examines the diverse and complex regulatory functions of the cistronic myomiRs miR-133, -1 and -206 in numerous tissues. The myomiRs are intimately involved in the regulation of many processes of muscle development, muscle cell metabolism and homeostasis. Indeed some of the myomiRs are critical cell factors that commit stem cells onto the path of muscle cell differentiation and development, and their removal can elicit de-differentiation of committed muscle cells to an undifferentiated state. This centrality of cell regulatory functions suggests that, by necessity, these miRs would also be involved in redeveloping and repairing tissue after damage or injury, and that dysfunctional expression of myomiRs would play important roles during disease states. Furthermore, individual myomiRs have functional roles in the development of numerous non-muscle cells and tissues, beyond their original classification as muscle-specific factors, and hence the observation that myomiRs have roles in an increasing number of different cancer types should perhaps not be surprising. Whilst the myomiRs can display either tumor suppressor or tumor stimulator roles in different cells and tissues, independent cellular function assays confirm that the altered expression of the myomiRs typically correlates with the potentiation of cancer severity. This apparently contradictory ability of miRs to cause tumor suppression or tumor stimulation actions in different tissues relates to the multiple regulatory pathway genes targeted by each miR and the specific regulatory functions targeted in each tissue type. Interestingly, this ambiguity parallels the alternate roles of key signalling pathway regulatory genes in cancers, for example the increased expression of members of the FOX family of genes can cause either tumor suppression or tumor stimulation in different cancer types[165]. Significantly, the number of validated targets of each of the myomiRs has increased greatly in recent years, yet the extent to which each myomiR, miR-133, miR-1 or miR-206, contributes to specific tumorigenesis or tumor progression must await fuller clarification and integration with complex cellular regulatory pathway processes which are not yet fully defined.


P- Reviewer: Hatzaras I, Hosoda T, Yang BF S- Editor: Ji FF L- Editor: A E- Editor: Wang CH

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