Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Table 1 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b

Factor(s)	Regulation	Regulator	Tissue/cell	Ref.
Fish and lower vertebrates: Development and regeneration
Ttk protein kinase (mps1)	Upregulated mps1: a target of miR-133	Downregulation of miR-133 by Fgf	Regeneration of Zebrafish caudal fin (appendage)	[68]
RhoA	Downregulation of RhoA mRNA	Upregulation of miR-133b expression	Regenerating adult zebrafish spinal cord, axon outgrowth	[69]
RhoA	Downregulation of RhoA protein	Upregulation of miR-1 and miR-133 expression	Zebrafish muscle gene expression and regulation of sarcomeric actin organization	[166]
Cell cycle factors mps1, cdc37 and PA2G4, and cell junction components cx43 and cldn5	Upregulated mps1, cdc37, PA2G4, cx43, cldn5	Downregulated miR-133(a1) stimulates cardiac cell regeneration	Regenerating zebrafish cardiac muscle	[167]
miR-133b	MiR-133b found in developing somites, little in CNS tissues		Whole zebrafish embryos - normal development	[168]
SRF activates muscle specific genes and miRs;	MiR-1 targets HDAC4, promoting myogenesis	In contrast, miR-133a represses SRF, enhancing myoblast proliferation	X. 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; MEF2	Subunits UNC-29, UCR-63, and MEF2 downregulated	miR-1 upregulated	C. elegans muscle at the neuromuscular junction	[34]
Mammalian pluripotent cells
Muscle-specific microRNAs: miR-1 and miR-133a	MiR-1 and miR-133a have opposing functions during differentiation of progenitor cardiac muscles	Muscle-specific	Promotion 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 effects	Dll-1 translationally repressed	miR-1 upregulation, promotes cardiomycete differentiation	Mouse and human ES cell differentiation into muscle	[13]
SRF-/- EBs reflecting the loss of hematopoietic lineages in the absence of SRF	Early endoderm markers, Afp and Hnf4α: strongly down regulated	Increased miR-1 and miR-133a relieve the block on mesodermal differentiation	Mouse endoderm	[13]
Blood cell -specific genes, such as Cd53, CxCl4, and Thbs1, dramatically down regulated	Cd53, 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 EBs	Nodal stimulated expression of endoderm markers Afp and Hnf4α in control EBs. Dramatically lower levels in mES(miR-1)- and mES(miR-133a)- EBs	miR-1 or miR-133 can each function as potent repressors of endoderm gene expression	mES cells, that lack either miR-1 or miR-133(a) during differentiation into EBs	[13]
IGF-1	IGF-1 signalling and miR-133 co-regulate myoblast differentiation via a feedback loop	IGF-1 upregulates miR-133;	Myogenic differentiation of C2C12 myoblasts; Mouse during development from embryonic to mature skeletal muscle	[24]
IGF-1R		miR-133 downregulates IGF-1R
IGF-1	IGF-1 signalling and miR-1 coregulate differentiation of myoblasts via a feedback loop	IGF-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 promoter	Reversine 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 Ezh2	Reduced expression of myogenin, MyoD, Myf5 and Aurora A and B kinases
FZD7 and FRS2	miR-1 promotes cardiac differentiation; miR-1 targets FZD7 and FRS2	Activitation of WNT and signalling cause MCPs differentiation into cardiomyocytes	Mouse and human ES cells	[169]
miR-206/133b cluster	PAX7 gene expression unchanged;	miR-206/133b cistron knock-out mice cells	Muscle 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 alpha	Repression of Idl-3 protein expression	miR-206 up-regulated	Mouse skeletal muscle differentiation	[42]
	Repression of p180 subunit of DNA polymerase alpha
MEF2 transcription factor	MEF2 activates of miR-1-2 and 133a-1 transcription; binds muscle-specific enhancer	Bicistronic primary transcript of miR-1-2 and 133a-1	Development of mammalian skeletal muscle	[9]
MRFs, Myf5, MyoD, Myogenin and MRF4	Myf5 essential for miR-1 and miR-206 expression during skeletal muscle myogenesis	Forced expression of MRFs in neural tube induces miR-1 and miR-206 expression	Chicken and mouse embryonic muscle	[171]
PTB and neuronal homolog nPTB, exon splicing factors	Downregulation of PTB protein by miR-133 (and miR-206)	Concurrent upregulation of miR-133 and induction of splicing of several PTB-repressed exons	During myoblast differentiation, microRNAs control a developmental exon splicing program	[172]
BDNF	BDNF downregulated	miR-206 upregulated	Differentiation of C2C12 myoblasts into myotubes	[48]
Fstl1 and Utrn	Fstl1 and Utrn downregulated	miR-206 upregulated	Skeletal muscle differentiation	[40]
Utrophin A (muscle)	Utrophin A down-regulated by both miRs	Upregulated miR-133b, miR-206	C2C12 mouse myoblasts, mouse soleus muscle	[173]
CNN3 gene	Negative correlation between miR-1 expression and CNN3 mRNA expression	Normal skeletal muscle	Tongcheng (Chinese) and Landrace (Danish) pigs	[174]
FGFR1 and PP2AC, members of ERK1/2 signalling pathway	miR-133 (a and b) activities increase during myogenesis	miR-133 directly downregulates expression of FGFR1 and PP2AC	Mouse C2C12 myoblast cells	[31]
ERK1/2 signalling pathway activity	ERK1/2 signalling activity suppresses miR-133 expression	Downregulation of expression of miR-133	A reciprocal mechanism for regulating myogenesis
BAF chromatin remodelling complex (BAF60a, BAF60b and BAF60c)	Positive inclusion of BAF60c in the BAF chromatin remodeling complex	Expression of miR-133 and miR-1/206	Progression of developing somites in chick embryos	[63]
BAF chromatin remodelling complex	Negative regulation of BAF60a and BAF60b; exclusion from BAF chromatin remodelling complex	Expression of miR-133	Progression of developing somites in chick embryos	[63]
BAF chromatin remodelling complex	Exogenous upregulation of BAF60a and BAF60b		Delay in developing somites in chick embryos	[63]
Mitochondrial UCP2 and UCP3	MyoD activates miR-133a expression which in turn directly downregulates UCP2 mRNA	Feedback network involving MyoD-miR-133a-UCP2	Mouse skeletal and cardiac muscles; UCP2 imposes developmental repression	[56]
Mitochondrial UCP2 and UCP3	Exogenous overexpression of myogenin and MyoD transcription factors	Strong increase in UCP3 promoter, expression, weak effect at the UCP2 promoter	Mouse C2C12 myoblasts	[57]
Proliferating myogenic skeletal muscle cells
MiR-206/133b cluster	MiR-206/133b cluster is not required for survival and regeneration of skeletal muscle	Muscle regeneration proceeds in Mdx mice in vivo	miR-206/133b cistron knock-out mice	[170]
Enhanced translation of specific mitochondrial genome-encoded transcripts	miR-1 enters muscle mitochondria and binds mtRNA targets along with Ago factor	Increased expression of mtRNA targets	Proliferating myogenic skeletal muscle cells after muscle injury	[53]
mTOR (serine/threonine kinase)	MyoD stability regulated by mTOR	Regulates miR-1 expression via MyoD availability	Regenerating mouse skeletal muscle and differentiating myoblast cells	[32]
AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathways	mTORC regulates timing of satellite cell proliferation during myogenesis	Knockdown of mTORC reduces miR-1 expression	Myogenenic satellite SCs proliferating and differentiating into myogenic precursors following rat skeletal muscle injury	[58]
HDAC4 regulates Pax7-dependent muscle regeneration	Pax7 stimulates SCs differentiation toward the muscle lineage, and limits adipogenic differentiation	HDAC4 upregulated in SCs differentiating into muscle cells	Myogenenic satellite SCs	[175]
pcRNA encoded by the H strand of the rat mitochondrial genome	Introduction of mt pcRNAs into injured muscle restoring mitochondrial mRNA levels; Intramuscular ATP levels were elevated after pcRNA treatment of injured muscle	Enhanced organellar translation and respiration; similarly reactive oxygen species were reduced; Resulted in accelerated rate of wound resolution	Injured 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-133	Reprogrammed human fibroblasts show sarcomere-like structures and calcium transients; Some cells have spontaneous contractility	Forced over-expression of GATA binding protein 4, Hand2, T-box5, myocardin, and microRNAs miR-1 and miR-133	Human embryonic and adult fibroblasts activated to express cardiac markers	[15]
SRF, MyoD and Mef2 transcription factors	miR-1-1 and miR-1-2	miR-1 genes upregulated;	Cardiac muscle precursor cells	[30]
	During cardiogenesis miR-1 genes titrate critical cardiac regulatory proteins, control ratio of differentiation to proliferation	Elevated miR-1 targets downregulation of Hand2
Histone deacetylase inhibitor, trichostatin A forces differentiation, yet reduced miR-1 and miR-133a	miR-1 and miR-133a reduce cardiac specific Nkx2.5 protein and Cdk9	miR-1 and miR-133a increase during spontaneous differentiation of cardiac myoblasts	Mouse cardiac stem cells (ES cells)	[10]
Specific inhibition of HDAC4 modulates CSCs to facilitate myocardial repair	Positively proliferative myocytes increased in MI hearts receiving HDAC4 downregulated CSCs	CSCs with downregulated HDAC4 expression improved ventricular function, attenuated ventricular remodeling, promoted regeneration and neovascularization in MI hearts	Mouse CSCs transplanted into MI mouse hearts	[177]
Snai1	Overexpression of miR-133a (miR-133), Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and MyocD improved cardiac cell reprogramming from mouse or human fibroblasts	miR-133a directly represses Snai1 expression, which silences fibroblast signatures; a key molecular process during cardiac reprogramming	Mouse/human fibroblasts more efficiently reprogrammed into cardiomycete-like cells	[16]
β1AR signal transduction cascade	Adenylate cyclase VI and the catalytic subunit of the cAMP-dependent PKA are components of β1AR transduction cascade	miR-133 directly targets β1AR, Adenylate cyclase VI and PKA	TetON-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 GPx	miR-133 produced a reduction of ROS and MDA levels, and an increase in SOD activity and GPx levels	Overexpression of miR-133, a recognized anti-apoptotic miRNA	In vitro rat cardiomyocytes	[18]
Caspase-9	miR-133 directly suppresses caspase-9 expression resulting in downregulation of downstream apoptotic pathways	Overexpression of miR-133	In vitro rat cardiomyocytes	[18]
Spred1	miR-1 directly targets Spred1	miR-1 is upregulated in hCMPCs during angiogenic differentiation	hCMPCs	[178]
miRNA-1 and miRNA-133a	miRNA-1 and miRNA-133a have antagonistic roles in the regulation of cardiac differentiation	Forced overexpression of miR-1 alone enhanced cardiac differentiation, in contrast overexpression of miR-133a reduced cardiac differentiation, compared to control cells	Pluripotent 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 Hand2	Cardiac myocytes show defective heart development, altered cardiac morphogenesis, channel activity, and cell cycling	miR-1-2-/- gene knockout	Cardiac myocytes with knockout of both miR-1-2 genes	[180]
mt-COX1 mRNA	3’-UTR of mt-COX1 mRNA bound by miR-181c and Ago1 factor	Overexpression of miR-181c significantly decreased mt-COX1 protein, but not mt-COX1 mRNA level	Overexpression of miR-181c increased mitochondrial respiration and reactive oxygen species in neonatal rat ventricular myocytes	[54]
mt-COX1 mRNA	In vivo elevation of miR-181c in rat heart, reduces levels of mt-COX1 protein	Results in reduced capacity for strenuous exercise and evidence of heart failure	Rat cardiac muscle	[55]
Carvedilol, a β-adrenergic blocker	Induces upregulation of miR-133	Cytoprotective effects against cardiomyocyte apoptosis	Rat cardiac tissue, in vivo	[18]
GLUT4, and SRF	Both miRs downregulate SRF and KLF15	Both miR-133a and miR-133b target KLF15	Mouse cardiac myocytes	[181]
GLUT4 expression	Both basal and insulin-stimulated glucose uptake are increased	KLF15	Mouse muscle cell lines	[182]
MEF2 transcription factor	MEF2 directly activates transcription of miR-1-2 and 133a-1 binding muscle-specific enhancer between the genes	Bicistronic primary transcript of miR-1-2 and 133a-1	Development of mammalian cardiac muscle	[9]
Myocardium tissue	Enriched in miR-1, miR-133b, miR-133a		Heart structures of rat, Beagle dog and cynomolgus monkey	[183]
Gelsolin	One common miR-133a isomiR targets gelsolin gene more efficiently than standard isomer; New second rat miR-1 gene	Many isomiRs were detected by deep sequencing at higher frequency than the canonical sequence in miRBase	miRNA/isomiR expression profiles in the left ventricular wall of rat heart	[184]
CTGF	CTGF downregulated by both miRs	Exogenous upregulation of miR-133b (and miR-30c)	Cultured cardiomyocytes and ventricular fibroblasts	[185]
MT1-MMP	miR-133a upregulated	miR-133a targets MT1-MMP	Human left ventricular fibroblasts	[186]
Injured and regenerating cardiac muscle
SERCA2a	Akt/FoxO3A-dependent pathway	Downregulation of miR-1 expression in failing heart muscle	Failing mouse heart muscle	[187]
	Activated SERC2a reduces phosphorylation of FoxO3a, allowing entry to nucleus and activation of miR-1 expression
IGF-1	IGF-1 signalling and miR-1 co-regulate differentiation of myoblasts via a feedback loop	IGF-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 Bmf	Only miR-133a expression enhanced under in vitro oxidative stress	miR-133a targets proapoptotic genes Bim and Bmf	Rat adult CPCs	[188]
			miR-1 favors differentiation of CPCs, whereas
Bim and Bmf	CPCs overexpressing miR-133a improved cardiac function by reducing Bim and Bmf	CPCs overexpressing miR-133a improved cardiac function, increasing vascularization and cardiomyocyte proliferation, reduced fibrosis and hypertrophy	CPCs overexpressing miR-133a in rat myocardial infarction model	[188]
MT1-MMP activity increased in both. Ischemia and reperfusion regions	Interstitial miR-133a decreased with ischemia in vitro and in vivo; reperfusion returned to steady-state	Phosphorylated Smad2 increased within the ischemia-reperfusion region	Ischemia-reperfusion Yorkshire pigs (90 min ischemia/120 min reperfusion)	[186]
Cardiovascular disease
CNN2	Strong upregulation of CNN2 expression	miR-133b downregulated; miR-133b directly targets CNN2	Pre-inflammatory events in diseased cardiac tissues	[65]
Circulating platelet derived microparticles	Elevated miR-133		Patients with stable and unstable coronary artery disease	[189]
Acute MI causes upregulation of circulating serum miRs	miR-1, -133a, -133b, and -499-5p were about 15- to 140-fold elevated over control		Acute STEMI patients and experimental mouse MI model	[190]
Circulating miRNAs in serum of cardiovascular disease patients	Released miR-1 and miR-133a are localized in exosomes, and are released by Ca(2+) stimulation	Levels of miR-1, miR-133a, reduced in infarcted mouse myocardium model heart	miR release indicates myocardial damage	[191]
LVM after valve replacement in aortic stenosis	microRNA-133a is a significant positive predictor of LVM normalisation	miR-133 is a key element of the reverse remodelling process	Patients following valve replacement	[192]
Circulating levels of miR-133a	Elevated miR-133a (11-fold)		Troponin-positive acute coronary syndrome patients	[193]
Circulating levels of miR-133a	Elevated miR-133a	Improved potential regression of Left Ventricular Hypertrophy after valve replacement	Patients with aortic stenosis surgery	[194]
Apelin treatment reduces elevated circulating miRs	Elevated miR-133a, miR-208 and miR-1 reduced	High-fat diet elevated miRs and increased left ventricular diastolic and systolic diameters, and wall thickness	Obesity-associated cardiac dysfunction in mouse model	[195]
NAC treatment	Expressed miR-1, miR-499, miR-133a, and miR-133b were strongly depressed in the diabetic cardiomyocytes	NAC restored expression of miR-499, miR-1, miR-133a, and miR-133b significantly in the myocardium	Diabetic rat hearts	[196]
Myocardial junctin elevated	miR-1 targets junctin	NAC reduces junction levels	Development of diabetic cardiomyopathy in rat hearts	[196]
CAD associated ischemic heart failure	miR-133 expression decreased with increased severity of heart failure		Patients with CAD	[197]
Runx2	miR-133a targets Runx2		Transition of VSMCs to osteoblast-like cells	[198]
Increased alkaline phosphatase activity, osteocalcin secretion and Runx2 expression	miR-133a was decreased during osteogenic differentiation		Transition of VSMCs to osteoblast-like cells	[198]
Circulating miR-133a and 208a levels	Cardiac muscle-enriched microRNAs (miR-133a, miR-208a) elevated		Patients with coronary artery disease	[199]
Hypertrophic cardiac muscle
Cx43 increased	miR-1 targets Cx43	Downregulation of miR-1 mediates induction of pathologic cardiac hypertrophy	Hypertrophic rat cardiomyocytes in vitro and in vivo	[200]
Cx43 downregulated	miR-1 targets Cx43	Cx43 protein downregulated in miR-1 Tg mice compared to WT mice	Cardiac-specific miR-1 transgenic (Tg) mouse model	[201]
Twf1 upregulated	miR-1 targets Twf1	Strong downregulation of miR-1 in pathologic hypertrophic cardiac cells compared to normal, induces Twf1 expression	In vivo in hypertrophic mouse left ventricle; and in vitro in phenylephrine-induced hypertrophic cardiomyocytes	[202]
RhoA, Cdc42, Nelf-A/WHSC2	Increased levels of RhoA, Cdc42, Nelf-A/WHSC2	Reduction miR-133a	Hypertrophic cardiac muscle	[6]
Calcineurin, agonist of cardiac hypertrophy	Increased Calcineurin activity;	Reduced miR-133a;	Hypertrophic cardiac muscle;	[203]
	Cyclosporin A inhibits calcineurin	Prevents miR-133 down-regulation	Cardiac hypertrophy reduced
NFATc4	NFAFc4 targetted by miR-133a	miR-133a	Cardiomyocyte hypertrophic repression	[204]
Interdependent Calcineurin-NFAT and MEK1-ERK1/2 signalling pathways in cardiomyocytes	MEK1-ERK1/2 signalling augments NFAT and NFAF gene expression; Activated calcineurin activates NFAT, inducing cardiac hypertrophy	MEK1 is part of mitogen-activated protein kinase (MAPK) cascade; MEK1 activates ERK directly	Hypertrophic growth response of mouse cardiomyocytes	[205]
Innervating skeletal muscle
Innervated skeletal muscle	MyoD, Myf5, Mrt4, nAChRα	Myogenin expression	Mouse skeletal muscle	[50,51]
	Each is strongly repressed
Denervated muscle (unstimulated)		Myogenin expression up-regulated MyoD, Myf5, Mrt4, nAChRα	Mouse skeletal muscle	[51]
		All strongly stimulated
Electrically stimulated - Denervated muscle	Myogenin, MyoD, Myf5, Mrt4, partly stimulated; nAChRα inhibited		Mouse skeletal muscle	[51]
HDAC4	miR-1 promotes myogenesis by targetting HDAC4	miR-133 enhances myoblast proliferation by targetting SRF	Skeletal muscle proliferation and differentiation in myoblast cultures	[7]
SRF
Neural activity effect on muscle (HDAC4 - MEF2 Axis)	Loss of neural input leads to concomitant nuclear accumulation of HDAC4	HDAC4 inhibits activation of muscle transcription factor MEF2; results in progressive muscle dysfunction	MEF-2 activity strongly inhibited in denervated mouse skeletal muscle and in ALS muscle	[49]
Innervation and formation of airway smooth muscle	Sonic hedgehog (Shh) /miR-206/ BDNF	Shh signalling blocks miR-206 expression, which in turn increases BDNF protein	Shh coordinates innervation and formation of airway smooth muscle	[206]
nAChR subunits (UNC-29 and UNC-63); retrograde signalling	Subunits UNC-29, UCR-63 and MEF2 downregulated	miR-1 upregulated	C. elegans muscle at the neuromuscular junction	[34]
MEF2	Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulated	miR-206 upregulated	Rat skeletal muscle/re-innervating muscle	[43]
HDAC4	HDAC4 (miR-206 target, prospective miR-133b target) downregulated	miR-206/-133b upregulated (and miR-1/-133a downregulated)	Mouse fast twitch skeletal muscle/re-innervating muscle	[12]
Regenerating injured muscle
Hnrpu and Npy downregulated	miR-1 upregulated	miR-1, -133a, downregulated 1 mo after denervation, then increased 2 × at 4 mo after re-innervation	Rat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation	[43]
Ptprd downregulated	miR-133a upregulated
Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulated	3 × increase in miR-206 1 mo later, after reinnervation; elevated at least 4 mo	Predominant type II fiber at 4 mo, after nerve re-innervation	Rat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation	[43]
PP2A B56a	PP2A B56a downregulated	133a upregulated	Canine heart failure model: myocytes	[207]
CaMKII-dependent hyperphosphorylation of RyR2	VF myocytes had increased reactive oxygen species and increased RyR oxidation	miR-1 upregulated	Canine post-myocardial infarction model	[208]
Collagen upregulated	TGF-b1 and TGFbRII: upregulated	miR-133a or miR-590: downregulated	Canine model of acute nicotine exposure. Atrial fibrosis in vivo; cultured canine atrial fibroblasts in vitro	[209]
miR-208 upregulated	miR-1 and miR-133a downregulated		Human MI compared to healthy adult hearts	[210]
Myogenic proteins, MyoD1, myogenin and Pax7	Induced expression of MyoD1, myogenin and Pax7 several days after miR injection	Exogenous injection of miR-1, -133 and -206 promotes myotube differentiation	Regenerating injured mouse skeletal muscle	[211]
Cyclin D1/ Sp1	Cyclin D1/ Sp1 downregulated	miR-1/133 upregulated	Regenerating rat skeletal muscle	[212]
PRP, source of pro-inflammatory cytokines	Stong 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-cristallin	Stimulated 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 TWEAK	TWEAK upregulated	miR-1-1, miR-1-2, miR-133a, miR-133b and miR-206 downregulated	Degenerating/wasting mouse skeletal muscle	[59]
HMOX1 mediated by codependent inhibition of c/EBPδ binding to myoD promoter	HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing	Downregulation 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-206	Downregulation of MyoD, myogenin and myosin, and disturbed formation of myotubes. Upregulation of SDF-1 and miR-146a
Dystrophic muscular disease
Circulating serum microRNAs	miR-1, miR-133a, and miR-206 highly abundant in Mdx serum	miR-1, miR-133a, and miR-206 downregulated or modestly upregulated in muscle	Muscle tissue from patients with Duchenne muscular dystrophy (Mdx)	[213]
Laminin α2 chain deficiency	miR-1, miR-133a, and miR-206 are deregulated in laminin α2 chain-deficient muscle	Laminin α2 chain-deficient mouse	Congenital muscular dystrophy type 1A tissue	[214]
Dystrophic process advances from prominent inflammation with necrosis and regeneration to prominent fibrosis	Deficiency in calpain leads initially to accelerated myofiber formation followed by depletion of satellite cells	Pax7-positive SCs highest in the fibrotic patient group; correlated with down-regulation of miR-1, miR-133a, and miR-206	Muscle 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 heart	Normal skeletal muscle and heart development	Mdx 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 hybridization	Only miR-206 showed an over-expression in majority of DM1 patients	No 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 regeneration	HDAC inhibitors can activate FAPs towards muscle regeneration	Inhibition of HDAC induces MyoD and BAF60C expression, which causes up-regulation of miR-1-2, miR-133, and miR-206 expression	Early stage disease dystrophic mouse muscles, regeneration of myofibres	[62]
TDP-43	TDP-43 interacts with miR-1/-206 isomers, but not miR-133 isomers	Depleted miR-1/-206 allow targets IGF-1 and HDAC4 to accumulate in ALS muscle	Mouse ALS model injured motor neurons and muscle	[33]
Inflammation response in muscle
Inflammatory myopathies	Increased expression of TNFα	Associated with decreased expression of miR-1, miR-133a, and miR-133b	Inflammatory myopathies including dermatomyositis, polymyositis, and inclusion body myositis	[64]
hBSMCs sensitized with IL-13	Increased muscle RhoA	Reduction of muscle miR-133a	Sensitized human bronchial smooth muscle cells (hBSMCs)	[218]

IGF: Insulin-like growth factor; IGF-1R: IGF-1 receptor; MRFs: Muscle regulatory factors; PTB: Polypyrimidine tract-binding protein; Fstl1: Follistatin-like 1; Utrn: Utrophin; mTOR: Mechanistic target of rapamycin; pcRNA: Polycistronic RNAs; SRF: Serum response factor; Snai1: Snail family zinc finger-1; β1AR: β-adrenergic receptor; PKA: Protein kinase A; MDA: Malondialdehyde; Spred1: Sprouty-related EVH1 domain containing protein 1; mt-COX1: Mitochondrial cytochrome c oxidase subunit 1; SERCA2a: Sarcoplasmic reticulum calcium ATPase 2a; LVM: Left ventricular mass; NAC: N-acetylcysteine; CAD: Coronary artery disease; StAR: Steroidogenic acute regulatory protein; mES: Mouse embryonic stem; EBs: Endodermal bodies; SCs: Stem cells; CSCs: Cardiac stem cells; MI: Myocardial infarcted; hCMPCs: Human-derived cardiomyocyte progenitor cells; VSMCs: Vascular smooth muscle cells; CPCs: Cardiac progenitor cells; STEMI: ST-segment elevation MI.

Table 2 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b in other precursor cells and tissues

Factor(s)	Regulation	Regulator	Tissue/cell	Ref.
Nerve tissues
Pitx3	Pitx3 downregulated	miR-133b	Mammalian midbrain DNs	[73]
Exosome-mediated transfer of miR-133b from MSC to brain astrocytes	miR-133b transfer from multipotent mesenchymal stromal cells to neural cells	miR-133b upregulated	Mouse MSCs to neural cells	[47]
Ctgf and RhoA	Ctgf and RhoA downregulated	miR-133b upregulated	Multipotent MSCs/Rat brain parenchymal cells	[72]
miR-133b null mice: Striatum dopamine levels unchanged, Pitx3 expression unaffected; motor coordination unaltered	miR-133b has no significant role on mDA neuron development and maintenance in vivo	Normal numbers of mDA neurons during development and aging of miR-133b null mice	Mouse mDA neuron development in -/-miR-133b mutant mice	[45]
Acute or chronic morphine administration, or morphine withdrawal	miR-133b levels not affected		Rat VTA/ nucleus accumbens shell	[219]
GPM6A, a neuronal glycoprotein	microRNA-133b upregulation	Reduction in gmp6a at mRNA and protein level. Cell filopodium density was reduced	Hippocampus and prefrontal cortex of neonatal male rats stressed when in utero	[220]
Tac1 gene (neurotransmitter substance P)	Tac1 downregulated	miR-206 upregulated	MSCs-derived neural cells	[221]
Ketamine (antidepressive) administration	BDNF, a direct target gene of miR-206, was upregulated	miR-206 was downregulated by ketamine	Rat hippocampus tissue	[222]
Adipogenic tissues
IGF-1 and IGF-1R	IGF-1 signalling and miR-133b co-regulate ADSC differentiation via a feedback loop	miR-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
Pdrm16	miR-133a directly targets Prdm16.	Downregulation of miR-133 resultsin differentiation of pre-adipocyte precursors into BAT	Mouse adipocyte differentiation to BAT	[74]
Pdrm16	miR-133 directly targets Prdm16	Downregulation of miR-133 resulted in differentiation of pre-adipocyte precursors into BAT	Mouse primary brown adipocyte (and myogenic) progenitor cells - differentiate into BAT or SAT	[75]
Pdrm16	miR-133 targets Prdm16 controlling brown adipose determination in skeletal muscle satellite cells	miR-133 downregulates Prdm16	Adult mouse skeletal muscle stem cells (satellite cells) differentiate into BAT	[76]
HDAC4 downregulation directs SCs towards adipocyte differentiation	Brown adipose master regulator Prdm16 is upregulated, while its inhibitor miR-133 is also downregulated	HDAC4 downregulated in SCs differentiating into adipocyte progenitor cells	Myogenenic satellite SCs	[175]
GLUT4 expression	Both basal and insulin-stimulated glucose uptake are increased	KLF15	Mouse 3T3-L1 preadipocytes differentiating into adipocytes	[182]
Intrinsic insulin resistance	Elevated miR-133b	Undefined role	Adipose tissue of women with PCOS	[223]
Upregulation of LIM homeobox 8 and Zic family member 1 and downregulation of Homeobox C8 and Homeobox C9	Undefined relation of upregulated miR-206, miR-133b	Undefined relation with parallel upregulation of brite/beige markers, TBX1 and TMEM26	Human BAT from the supraclavicular region	[224]
Obesity development	Downregulation of miR-133b, miR-1	Undefined role	Adipose tissue from obese male C57BLJ6 mice	[225]
LXRα regulation of lipogenic genes	miR-1/miR-206 represses LXRα expression at both mRNA and protein levels	miR-1/miR-206-induces a decrease in lipogenic gene levels and lipid droplet accumulation	Mouse hepatocytes	[226]
Osteogenic tissues
Development of bone on organic or inorganic substrates		miR-133 differentially expressed in osteoblasts grown on different substrates	Osteoblast	[227]
Runx2	miR-133 directly down-regulates Runx2	miR-133 up-regulated	Osteogenic differentiation from C2C12 mesenchymal cells	[228]
HDAC4	HDAC4 downregulates Runx2	miR-1 targets HDAC4, increasing Runx2 activity	Chondrocyte proliferation in cartilage growth plate	[77]
Aggrecan	miR-1 promotes late-stage differentiation of growing cartilage cells	miR-1 targets Aggrecan gene expression	Chicken chondrocytes and human HCS-2/8 cells	[78]
Alveolar cells
VAMP2/ lung surfactant secretion	miR-206 targets VAMP-2	miR-206 overexpression decreased lung surfactant secretion	Lung alveolar type II cells	[229]
Hormonal regulation
L-thyroxine	miR-206/miR-133b downregulated	L-thyroxine treatment	L-thyroxine treated hypothroidic skeletal muscle from thyroidectomized patients	[230]
	miR-206/miR-133b upregulated	-	Hypothroidic human skeletal muscle
Thyroid hormone/TEAD1	Thyroid hormone inhibits the slow muscle phenotype by upregulation of miR-133a1 which downregulates TEAD1	miR-133a1 is enriched in fast-twitch muscle and regulates slow-to-fast muscle fiber type conversion	Mouse muscle	[231]
Thyroid hormone/miR-133a1 TEAD1	myosin heavy chain I expression downregulated	TH indirectly downregulates myosin heavy chain I via miR-133a/TEAD1	Mouse muscle	[232]
L-thyroxine	pre-miR-206 and pre-mir-133b downregulated	L-thyroxine	L-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 cardiomycetes	Downregulation KLF15, which downregulates GLUT4	Forced overexpression of miR-133a and miR-133b	Rat cardiac myocytes	[181]
Cardiac myocyte glucose metabolism	Upregulation KLF15, which upregulates GLUT4	Silencing endogenous miR-133	Rat cardiac myocytes	[181]
Metabolic control of glucose uptake by GLUT4 transporter	Downregulates KLF15, which results in downregulation of GLUT4 levels	Chronic heart failure has depressed miR-133a and -133b levels	Rat cardiac myocytes during chronic heart failure and cardiac hyperthrophy	[181]
Atrial natriuretic factor expression upregulation	Enhanced at LVH and dramatically increased at CHF stage	Both miR-133a and miR-133b downregulated at CHF stage	LVH and CHF in salt-sensitive Dahl rats	[181]
Estrogen	Estrogen replacement strongly decreased IGF-1 protein level in muscles at 1 wk		Ovariectomized rat skeletal muscle	[233]
Multiple targets	miR-133a upregulated in BTBR mice		Pancreatic 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 levels	miRNAs miR-1, miR-133a and miR-206 specifically expressed both in brown pre- and mature adipocytes	miRNAs miR-1, miR-133a and miR-206 were absent from white adipocytes	Mouse brown adipocytes	[235]
Foxl2	miR-133b targets Foxl2;	Foxl2 regulates StAR and CYP19A1 transcriptionally	Estradiol 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 astrocytes	miR-133b transfer from multipotent mesenchymal stromal cells to neural cells	miR-133b upregulated	Mouse multipotent MSCs to neural cells	[47]
Cell to cell transfer of exosome-enriched extracellular particles	mir-133b promotes neural plasticity and recovery of function after stroke induced damage	miR-133b upregulated	Rat multipotent MSCs via transfer of exosome-enriched extracellular particles	[72]
Transplanted stem cells
MSCs expressing miR-1	Upregulated miR-1	Increased rate of recovery, enhanced survival of transplanted MSCs and cardiomyogenic differentiation	Experimental ligation of the mouse left coronary artery to model myocardial infarction	[237]
Knockdown of Hes-1, member of Notch pathway	Upregulated miR-1 promotes the differentiation of MSCs into cardiac lineage	Role in survival of transplanted MSCs and cardiomyogenic differentiation	Mouse MSCs	[238]
Notch signalling and cardiomyocyte markers, Nkx2.5, GATA-4, cTnT, and Cx43	MSCs expressing exogenous miR-1		Mouse MSCs	[238]
Tissue inflammation
Selective release of miRs during inflammation into serum	miR-133 selectively released		Review	[239]
Inflammation and cancer	MicroRNA, free radical, cytokine and p53 pathways		Review	[240]
Immunological switch which shapes tissue responses	TWEAK/Fn14 pathway		Review	[241]
Tumor biology	HMOX1		Review	[242]
GM-CSF	Direct supression of GM-CSF expression by miR-133	Elevated expression of miR-133a/-133b during oxidative stress	Mouse alveolar epithelial cells during oxidative stress	[82]
PI3K/Akt and IGF-1 pathways	Activation of PI3K/Akt and IGF-1 pathway activities	Downregulation of miR-133a (and other miRs) by AOM/DSS induced chronic inflammation	Mouse model: AOM/DSS-induced colitis-associated gastro-intestinal cancer	[83]
CTGF, SMA, and COL1A1	Increased expression of CTGF, SMA and COL1A1, which are miR-133b targets	Strong downregulation of miR-133b (and other miRs)	TGF-β treated rabbit corneal fibroblasts; Recovering mouse cornea after laser ablation,	[70]
IL-10 and TGF-β	Exogenous IL-10 and TGF-β induces miR-133b expression	Upregulation of miR-133b	Human tolerogenic dendritic cells during maturation	[79]
IL-17-producing T-cells	Upregulation of Il17a/f gene expression	miR-133b/-206 cistron transcription occurs along with nearby Il17a/f gene expression	Immunocompetent mouse Th17 cells	[80]
NLRP3 inflammasome which processes IL-1β by caspase-1 cleavage	miR-133a-1 suppresses activation of inflammasomes via suppression of expression of mitochondrial UCP2	miR-133a-1 overexpression in cells increases caspase-1 p10 and IL-1β p17 cleavage,	Differentiated mouse THP1 cells	[81]
Concanavalin A-induced fulminant hepatitis		miR-133a is the most strongly differentially upregulated miR	Mouse liver following ConA injection	[243]
Infection/immune response to influenza virus (H1N2)	miR-206 expression		Experimental 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 PASMCs	miR-206 targets HIF-1α directly. Hypoxia-induced down-regulation of miR-206 promotes PH in PASMCs	Hypoxia-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 activity	Astrocyte-associated inflammation during recovery from chronic central nervous system injury	[246]
Indirectly: inflammatory cytokines (IL6, IL1B, CCL5)
Cellular factors influencing myomir expression/activity
miR-1/miR-133a
Skeletal muscle
Positive regulator	Negative regulator	Regulated target miR	Tissue/cell	Ref.
Myogenin, MyoD		Upregulates miR-1-1 and miR-133a-2	Primary human myoblasts; C2C12 cells	[11]
		Upregulates miR-1-2 and miR-133a-1
SRF, MyoD and MEF2		Upregulates miR-1-2	Muscle somites	[30]
MEF2		Upregulates miR-1 and miR-133a	Skeletal muscle	[9]
KSRP (part of Drosha and Dicer complexes)	miR-206 binds 3’-UTR of KSRP and inhibits its expression	KSRP upregulates miR-1 expression	Skeletal muscle	[35,37]
RNA-binding protein LIN28		LIN28 upregulates miR-1 expression; LIN28 promotes pre-miR-1 uridylation by ZCCHC11 (TUT4)	Cardiac muscle of patients with muscular dystrophy	[36]
	MBNL1	MBNL1 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-1	Cardiac muscle of patients with muscular dystrophy	[36]
CX43 and CACNA1C calcium channel	CX43 and CACNA1C both increased in both DM1-/DM2-affected hearts, contributing to the cardiac dysfunctions	CX43 and CACNA1C are direct targets of miR-1 repression	Cardiac muscle of patients with muscular dystrophy;	[36]
			CACNA1C and CX43 encode the main calcium- and gap-junction channels in heart
Utrophin A	miR-206 and KSRP are negative regulators of utrophin A	Overexpression of miR-206 promotes the upregulation of utrophin A, via the downregulation of KSRP	Normal 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
	Myostatin	Downregulates miR-1, miR-133a, miR-133b, miR-206	Mouse (35 d) pectoralis skeletal muscle	[29]
	SRF	Downregulates miRs-133a	Skeletal muscle	[1,3]
Prmt5 and Prmt4		Upregulates myomiR expression during differentiation	Mouse skeletal muscle	[247]
Smooth muscle
Sp-1 transcription factor	pERK1/2	Upregulates miR-133(a)	VSMCs	[248]
Brg1		Upregulates miR-133 (ChIP complex with SRF)	Smooth muscle	[249]
Cardiac muscle
GATA4, Nkx2.5, Myocardin, SRF		Upregulates miR-1 and miR-133a	Differentiating cardiac muscle	[5]
SRF plus Myocardin		Upregulates miR-1-1 and miR-1-2	Cardiomycetes	[30]
	Calcineurin	Downregulates miR-133a	Hypertrophic cardiac muscle	[203]
miR-206/ miR-133b
Skeletal muscle
Mrf5		Upregulates miR-1, miR-206	Skeletal muscle	[171]
Myogenin, MyoD		Upregulates miR-206	Primary human myoblasts; C2C12 cells	[11]
MyoD		Upregulates linc MD1 (encodes miR-133b)	Differentiating myoblasts	[11, 38]
		Binds to (E-box) enhancer of miR-206, miR-133b	skeletal muscle (mouse)	[12,40]
		Upregulates miR-206/miR-133b	Differentiated human foetal skeletal muscle cells	[250]
	FGF2 allows upregulation of Sp1/Cyclin D1	Downregulates p38-mediated miR-1/133 expression	Regenerating rat skeletal muscle	[212]
	Myostatin	Downregulates miR-133a, mir-133b, miR-1, and miR-206	Mouse (35 d) pectoralis skeletal muscle	[29]
	TWEAK downregulates myoD and MEF2c	Downregulates miR-1-1 and miR-133	Degenerating/wasting skeletal muscle	[59]
	HMOX1 downregulates MyoD and myogenin	Downregulates all myomiRs	Inflamed skeletal muscle	[60]
L-Thyroxine treatment		Downregulation of pri-miR-206 and pri-miR-133b	Human skeletal muscle	[230]
		No effect on miR-1/miR-133a pairs
Smooth muscle
p-ERK	Activated extracellular signal-regulated kinase p-ERK inversely correlated with VSMC growth	Downregulates miR-133 expression	VSMCs	[248]
Other tissues
Myogenin		Binds miR-206 enhancer (ChIP)	Fibroblast cell line:	[40]
IGF-I signalling		Upregulates miR-133b	Mouse Adipose derived stem cells	[71]
L-Thyroxine deficiency	Upregulated Col5a3	Strong upregulation of miR-133a and -133b	Hypothyroid mouse liver	[232]
	Downregulated Slc17a8, Gp2, Phlda1, Klk1d3, Klk1 and Dmbt1	Strong upregulation of miRs -1, -206
	Upregulated Vldlr and Akr1c19, and downregulated Upp2, Gdp2, Mup1, Nrp1, and Serpini2
L-Thyroxine treatment	Pre-miR-206 and Pre-miR-133b down-regulated	Upregulation of Gdp2 andMup1	Hypothyroid mouse liver in vivo, and in vitro mouse hepatocyte AML12 cells	[232]
PA2G4, mps1, cdc37, cx43, cldn5; cx43 is a miR-133 target	Upregulation of cell cycle factors mps1, cdc37, and PA2G4, and cell junction components cx43 and cldn5	Suppression of miR-133a1 stimulates cardiac cell proliferation	Regeneration of damaged Zebrafish cardiac muscle, associated with reduced miR-133a1	[167]
Fgf	Upregulated Fgf	Downregulates miR-133	Zebrafish regenerating fin blastema	[67]
SHP (nuclear receptor)	Downregulation of miR-206 in nuclear receptor SHP(-/-) mice		SHP(-/-) mice strain, mouse liver	[251]
AP1 transcription factor complex	AP1 induced miR-206 promoter transactivity and expression; this is repressed by YY1	ChIP analysis shows physical association of AP1 (c-Jun) and YY1 with miR-206 promoter	SHP(-/-) nuclear receptor mice strain, mouse liver	[251]
NR3B3	YY1 promoter transactivated by ERRgamma; this inhibited by SHP (NROB2)	Nuclear receptor ERRgamma (NR3B3) binding site on the YY1 promoter	Mouse 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-206	Mouse liver	[251]
Il17a/f locus	miR-133b and miR-206 expression	Coregulated with IL-17 production	αβ and γδ T cells	[80]

IGF: Insulin-like growth factor; MRFs: Muscle regulatory factors; PTB: Polypyrimidine tract-binding protein; Fstl1: Follistatin-like 1; Utrn: Utrophin; mTOR: Mechanistic target of rapamycin; pcRNA: Polycistronic RNAs; SRF: Serum response factor; Snai1: Snail family zinc finger-1; β1AR: β-adrenergic receptor; PKA: Protein kinase A; MDA: Malondialdehyde; Spred1: Sprouty-related EVH1 domain containing protein 1; mt-COX1: Mitochondrial cytochrome C oxidase subunit 1; SERCA2a: Sarcoplasmic reticulum calcium ATPase 2a; LVM: Left ventricular mass; NAC: N-acetylcysteine; CAD: Coronary artery disease; StAR: Steroidogenic acute regulatory protein; VTA: Ventral tegmental area; BAT: Brown adipose tissue; SCs: Stem cells; PCOS: Polycystic ovary syndrome; LVH: Left cardiac ventricular hypertrophy; CHF: Chronic heart failure; DNs: Dopaminergic neurons; mDA: Midbrain dopaminergic; AOM: Azoxymethane; DSS: Dextran sulfate sodium; PH: Pulmonary hypertension; PASMCs: Pulmonary artery smooth muscle cells.

Table 3 The deregulated expression of the canonical myomiRs in different cancers

MiR-1	MiR-206	MiR-133a	MiR-133b	Cancer type	Ref.
		+	+	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]
-	-			Chordoma	[90]
	+			Colon cancer	[116]
-				Colon cancer	[101]
		-		CRC	[104,136]
			-	CRC	[86,87]
			+/-	Liver metastasis compared to primary CRC	[118]
-			-	Colon cancer	[95]
		-	-	Progressive GIST	[281]
		-		HNSCC	[143]
			-	HNSCC	[114]
	-			EEC	[110]
		-		ESCC	[132]
-		-	-	ESCC	[94]
	-			Laryngeal SCC cells	[113]
-		-		MSSCC	[137]
		-		TSCC	[111,112]
-				HCC	[98]
+			+	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]
			-	NSCLC	[85,105]
-	-			Lung adenocarcinomas; NSCLC cells	[99]
		-	-	Lung carcinomas	[85,115,131]
-			-	Lung cancer	[95]
-			-	Lymphoma	[95]
		+		AML	[120,151]
		+		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]
-		-	-	Osteosarcoma	[91]
-			-	Ovarian cancer	[95]
		-		PDAC	[103]
		-		RCC	[138]
-	-			Rhabdomyosarcoma	[88,89]
-			-	Testicular cancer	[95]

¹DS: Deep sequencing; TCC: Transitional cell carcinoma; CRC: Colorectal cancer; GIST: Gastrointestinal stromal tumor; HNSCC: Head and neck squamous cell carcinoma; EEC: ERα-positive endometrioid adenocarcinoma; ESCC: Esophageal squamous cell carcinoma; MSSCC: Maxillary sinus squamous cell carcinoma; TSCC: Tongue squamous cell carcinoma; HCC: Hepatocellular carcinoma; NSCLC: Non-small-cell lung cancer; AML: Acute myeloid leukaemia; PDAC: Pancreatic ductal adenocarcinoma; RCC: Renal cell carcinoma.

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 motility	Epigenetic promoter hypermethylation reduces miR-1/-133a expression in (a subset of) human prostate tumors	Reduced 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 PTMA	miR-1 downregulation associated with upregulation of multiple cancer-related pathway processes	Reduced 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
HSPB1	HSPB1 restores oncogenic pathways in prostate cancer cells	Downregulates miR-1 expression	Progressive prostate cancer PCa cells	[252]
XPO6 and TWF1 (PTK9)	Inverse expression between miR-1, XPO6 and TWF1 proteins in prostate cancer cell lines	Downregulated miR-1 expression	Prostate cancer cell cultures	[253]
CCND2, CXCR4, and SDF-1α	Inverse expression between miR-1 and CXCR4 and SDF-1α protein levels in thyroid carcinomas	Strongly downregulated miR-1 expression in thyroid adenomas and carcinomas	Thyroid adenomas and carcinomas	[254]
MET	MET upregulated	Reduced miR-1	Colon cancer	[101]
		Reduced miR-1, -133b	Colon cancer	[87]
MET, Pim-1 (Ser/Thr kinase), FoxP1 and HDAC4	miR-1 downregulated,	MET, Pim-1, FoxP1 and HDAC4 are often upregulated in lung cancer	NSCLC tissue and A549 cell line	[100]
	miR-1 targets MET, Pim-1, and may regulate FoxP1 and HDAC4
Fibronectin1	Fibronectin1 upregulated	miR-1 downregulated	Laryngeal SCC Hep2 cells	[255]
Met, Twf1 and Ets1 and Bag4	Met, Twf1 and Ets1 and Bag4 activities upregulated	miR-1 downregulated	Mouse cutaneous squamous cell carcinomas	[256]
Mediator complex subunit 1 (Med1) and 31 (Med31)	Med1 and Med31 activation result in increased Met activity	Reduced miR-1; miR-1 targets Med 1 and Med 31	Osteosarcoma	[257]
NOTCH3 upregulates Asef expression, activating the Asef promoter, enhancing cell migration	NOTCH3 upregulated	Reduced miR-1; miR-1 targets NOTCH3	Colorectal tumor cells	[258]
Overexpression of PIK3CA correlates with low miR-1 expression in NSCLC tissues	71% of NSCLC samples had high PIK3CA expression	69% of NSCLC samples had low miR-1 expression	Predictors of lymph node metastasis in NSCLC tissues	[259]
SLUG expression downregulated by miR-1	Transcriptional repressor of E-cadherin, or an inducer of epithelial-to-mesenchymal transition	Overexpression of miR-1 induces morphological change from a mesenchymal to an epithelial character	NSCLC A549 cell line	[260]
SLUG expression high in chordoma tissue	miR-1 inhibited cell proliferation both time- and dose-dependently in chordoma	Transfection of MiR-1 inhibited Slug expression	mR-1 transfected chordoma cells	[261]
			Slug overexpressed in advanced chordoma tissues and chordoma cells
MET expression high in chordoma tissue	miR-1 downregulated 97% of chordoma samples	MiR-1 directly targets MET	Decreasing miR-1 expression levels correlated with severity of clinical prognosis	[262]
SRSF9/SRp30c	Exogenous upregulation of miR-1 expression	Novel apoptosis pathway involving SRSF9/SRp30c mediates tumor suppression	Bladder cancer (TCC) cells	[263]
ANXA2 is essential for glioblastoma growth and invasion	ANXA2 is highly abundant protein in glioblastoma-derived extracellular vesicles	miR-1 directly targets ANXA2;	Human Glioblastoma cells; miR-1 orchestrates glioblastoma extracellular vesicle function	[264]
		Reduced miR-1 in glioblastoma
EDN1	miR-1 downregulated in gastric cancer	miR-1 causes ET-1 silencing in gastric cancer cell lines	Gastric cancer tissue compared with adjacent normal tissue	[265]
EDN1	Elevated expression of EDN1 and reduced miR-1 level	miR-1 directly targets EDN1	Human liver cancer tissues	[266, 267]
Overexpressed EDN1	Enhanced in vitro cell proliferation and cell migration. Upregulation of several cell cycle/proliferation- and migration-specific genes	Upregulated UPR pathway mediators, spliced XBP1, ATF6, IRE1, and PERK at both RNA and protein levels	293T cells	[267]
AKT inhibitor diminished the unfolded protein response and eliminated EDN1-induced cell migration	EDN1 effects act via activation of the AKT pathway	Results to enhance the UPR and subsequently activate the expression of downstream genes	293T cells	[267]
Edn1	Induced steatosis, fibrosis, glycogen accumulation, bile duct dilation, hyperplasia, and HCC	Liver-specific edn1 expression	Transgenic Zebrafish liver	[267]
API5	API5 expression upregulated thus inhibiting apoptosis	miR-1 expression downregulated	Human liver cancer tissues	[268]
	Apoptosis activated, API5 reduced	Overexpression of miR-1	HepG2 liver cancer cells
Phosphorylation of ERK and AKT; LASP1	Overexpression of miR-1 inhibits phosphorylation of ERK and AKT and reverses EMT process via inhibition of MAPK and PI3K/AKT pathways	MAPK and PI3K/AKT pathways	Transgenic miR-1 expressing CRC cell lines	[269]
LASP1 expression upregulated	Upregulated LASP1 stimulates EMT resulting in cell proliferation and migration	miR-1 downregulated	Colorectal tumor tissue	[269]
PIK3CA	Increased expression of PIK3CA	Downregulated miR-1 expression in lung cancer	NSCLC tissue with poor patient prognosis	[259]
PIK3CA indirectly regulating pAKT and survivin proteins	Overexpressed miR-1 downregulated PIK3CA causing reduced pAKT and survivin proteins	Exogenously 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 adhesion	Ectopic expression of miR-1 and miR-145 downregulates VEGFA and AXL, respectively	Highly downregulated expression of miR-1, miR-133, miR-143 and miR-145 in gall bladder cancer	Gall bladder tumor samples and GBC NOZ cell line	[271]
lncRNA UCA1	Lnc RNA UCA1 upregulated in bladder cancer (TCC);	Downregulated miR-1 expression in bladder cancer (TCC); miR-1 targets lnc RNA UCA1 for downregulation	Human bladder cancer (TCC) tissue	[156]
	Inverse relationship between miR-1 and lnc UCA1
Downregulated miR-133a
Moesin	Moesin upregulated	Reduced miR-133a	HNSCC	[143]
ARPC5	ARPC5 upregulated	Reduced miR-133a	HNSCC	[272]
ARPC5 and GSTP1	ARPC5 and GSTP1 upregulated	Reduced miR-133a (and miR-206)	Lung carcinoma	[115]
IGF-1R, TGFBR1, and EGFR are downregulated	Restoration of ectopic-expression of miR-133a in NSCLC suppresses metastatic capacity	miR-133a inhibits cell invasiveness and cell growth via suppression of IGF-1R, TGFBR1 and EGFR	NSCLCs	[131]
	Low expression of miR-133a is characteristic of pancreas tissue	Reduced miR-133a	PDAC	[103]
CDC42	CDC42 upregulated causing downstream activation of PAKs	miR-133 downregulated	Gastric cancer tissues	[273]
GSTP1	Upregulated GSTP1	Downregulation of miR-133a in cancer	Bladder 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 specimens	GSTP1 upregulated	Reduced miR-133a	Bladder cancer (TCC) tissue	[144]
Actin-binding protein, FSCN1	Upregulated FSCN1;	Downregulation of miR-133a;	Bladder cancer (TCC) tissue	[274]
	Enforced downregulation of FSCN1 inhibits cell proliferation, migration and invasion	Forced UP exp of miR-133a inhibits cell proliferation, migration and invasion
EGFR/AKT signalling pathway	Upregulated EGFR;	Downregulated miR-133a;	Human MCF-7 and MDA-MB-231 breast cancer cell lines	[275]
	Activated pAkt-1	Enforced expression of miR-133a inhibits EGRF translation; causes inhibition of Akt protein phosphorylation and its nuclear translocation
Bcl-xL and Mcl-1 expression	Upregulated Bcl-xL and Mcl-1	Downregulated miR-133a correlated with tumor progression and poor patient prognosis;	Primary human osteosarcoma tissues;	[276]
			Osteosarcoma cell lines
E3 ubiquitin protein ligase	Downregulation of p21 and p53 proteins	Downregulated miR-133a	Primary CRC tissues	[277]
Enhanced sensitivity to doxorubicin and oxaliplatin	Enhancing apoptosis and inhibited cell proliferation	Ectopic upregulation of miR-133a	CRC cell lines	[277]
LASP1 upregulated	miR-133a expression downregulated	miR-133a targets LASP1	CRC tissues and cell lines	[278]
FTL protein upregulated	miR-133a expression downregulated	miR-133a targets downregulation of FTL protein	Patient breast cancer tissue	[279]
Increased sensitivity to chemotherapeutic drugs doxorubicin and cisplatin	Exogenous upregulation of miR-133a expression	Downregulation of FTL protein	Human MCF-7 breast cancer cells	[279]
Poor survival during breast cancer; upregulated FSCN1	Loss of miR-133a expression	FSCN1 is a direct target gene of miR-133a	Breast cancer tissue	[280]
FSCN1 downregulated	Restoration of miR-133a expression	Inhibited breast cancer cell growth and invasion	Breast cancer cell line	[280]
lncRNA Malat1/Srf/miR-133 regulatory loop	Malat1 transcript has a functional miR-133 target site, miR-133 acts as a competing endogenous RNA, regulating Malat1 levels	In vitro depletion of Malat1 in C2C12 cells reduces Srf activity, Srf is an enhancer of miR-133 expression; feed-back regulation loop involving miR-133	Mouse myoblast C2C12 cells	[164]
lncRNA MALAT1	MALAT1 is overexpressed in 46% of ESCC tissues, primarily in high-stage tumors, high expression correlates with lymph node metastasis	In vitro depletion of MALAT1 suppresses tumor cell proliferation, cell migration and invasion; G2/M phase arrest was induced and the ratio of apoptotic cells increased	Human ESCC	[162]
WIF1/lncRNA MALAT1	WIF1 (strong tumor suppressor) is systematically downregulated in glioblastoma	WIF1 down regulation correlates with strong upregulation of MALAT1. In vitro depletion of MALAT1 suppresses tumor cell proliferation	Glioblastoma	[163]
Downregulated miR-133b
Fascin-1 mRNA	FSCN1 upregulated	Reduced miR-133b	High-grade GIST tissue	[281]
BCL-2 family (MCL-1 and BCL2L2)	MCL-1 and BCL2L2 upregulated	Reduced miR-133b	Lung cancer	[85]
FAIM antiapoptotic protein and GSTP1	miR-133b directly targets FAIM and GSTP1	Downregulated miR-133b	miR-133b expression significantly downregulated in 75% of prostate cancer tumor specimens	[282]
Gli1	Gli1 upregulated	Gli1 inversely correlated with downregulated expression of miR-133b	Gastric cancer	[283]
Bcl-w and Akt1	Bcl-w and Akt1 proteins overexpressed significantly	miR-133b significantly downregulated	Bladder cancer tissues	[284]
		miR-133b downregulated in tumors compared to surrounding tissue	Gastric and esophageal adenocarcinomas	[285]
			Endometrial sarcoma, leiomyosarcoma, and mixed epithelial-mesenchymal tumors	[286]
Downregulated miR-206
Notch3/ miR-206	Downregulated Notch3, blocking of the anti-apoptotic activity of Notch3	Forced expression of miR-206 strongly induced apoptotic cell death via; also inhibited cell migration and focus formation	HeLa cells	[287]
Met	Upregulated Met	miR-206 downregulated	Human rhabdomyosarcoma	[288]
HGFR	Upregulated HGFR	miR-206 downregulated	Human breast cancer cells	[289]
KLF4	Upregulated KLF4	miR-206 downregulated	RK3E breast epithelium cells	[108]
KLF4; RAS-ERK signalling	Upregulated KLF4 promotes RAS-ERK signalling	miR-206 downregulated	TNBC cells	[290]
	Endogenous KLF4 binds the promoter regions stimulates expression of miR-206
RASA1 and SPRED1		miR-206 inhibits translation of the RAS pathway suppressors RASA1 and SPRED1	Suppression of RASA1 or SPRED1 increased levels of GTP-bound, wild-type RAS and activated ERK 1/2
VEGF	VEGF upregulated in Laryngeal SCC tissues	MiR-206 strongly downregulated in LSCC tissues	Laryngeal SCC cancer tissue and cells	[113]
VEGF	VEGF upregulated in ccRCC tissues	MiR-206 strongly downregulated in ccRCC tissues	ccRCC tissues assayed by Deep Sequencing	[291]
Cdc42, MMP-2 and MMP-9	Upregulated Cdc42, MMP-2 and MMP-9	miR-206 downregulated	Human breast cancer tissues	[292]
ERα	miR-206 directly targets ERα 3'-untranslated region	MiR-206 inhibited by ERα agonists, indicating a mutually (double) inhibitory feedback loop;	Estrogen stimulated breast cancer cell lines	[293]
		miR-206 downregulated		[109]
	Upregulated ERα		MCF-7 breast cancer cells	[294]
ERα	Upregulated ERα	miR-206 downregulated	EEC tissue	[110]
K-Ras	K-Ras is direct target of miR-206;	Low miR-206 potentiates metastases, and shorter overall survival	OSCC tissue samples and cell lines	[295]
	MiR-206 expression significantly downregulated and k-Ras upregulated on OSCC tissues
MiR-206	Enforced upregulated of miR-206 attenuated cell proliferation, increased apoptosis and inhibited cell migration and invasion	MiR-206 strongly downregulated in lung cancer tissues	Lung 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 phenotype	EGFR signalling represses estrogenic responses in MCF-7 cells by enhancing miR-206 activity	miR-206 downregulates steroid receptor co-activators SRC-1 and SRC-3 and GATA-3 transcription factor, directly	MCF-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 stage	miR-206 expression strongly downregulated	Correlates with tumor progression	Human gastric cancer tissue	[297]
CCND2	miR-206 expression strongly downregulated	Correlates with upregulation of CCND2 and cancer progression	Human breast cancer	[298]
			Human gastric cancer	[299]
MET	miR-206 expression strongly downregulated	Upregulation of MET	Papillary thyroid carcinoma	[300]
Prognostic signature of metastatic colorectal cancer	miR-206 expression strongly downregulated	Prognostic signature of metastases: miRs 21, 135a, 335, 206 and let-7a	Metastatic 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-3	miR-206 is a potent tumor supressor	p57 and Bax upregulated, and cleaved caspase-3 protein upregulated	Reduced apoptosis, and cell migration in HepG2 cells overexpressing miR-206
STC2, HDAC4, KLF4, IGF1R, FRS2, SFRP1, BCL2, BDNF and K-ras	Exogenous upregulation of miR-206 expression;	STC2, HDAC4, KLF4, IGF1R, FRS2, SFRP1, BCL2, BDNF, and K-ras downregulated strongly in SCG-7901 cells overexpressing miR-206	Gastric carcinoma SCG-7901 cells	[303]
	miR-206 is a potent tumor supressor		Reduced apoptosis, and cell migration in SCG-7901 cells overexpressing miR-206
Cyclin C, CCND1 and CDK4	Cyclin C, CCND1 and CDK4 upregulated in melanoma tissue;	hsa-miR-206 downregulated in melanoma tissue	Human 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 protein	Silencing of coronin expression reduced tumor cell migration and altered the cellular actin skeleton and cell morphology, but did not effect cell proliferation	Downregulated 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 APOBEC3	DND1 blocks miRNA interaction with 3'-UTR of specific mRNAs, restores protein expression; APOBEC3G binds DND1 counteracts repression and restores miRNA activity	APOBEC3G blocks DND1 to restore miR-206 inhibition of CX43 translation	Mouse cells	[306]
Advanced clinical stage, T classification, metastasis and poor histological differentiation		Significant association with decreased miR-206 expression	Paired human osteosarcoma and normal adjacent tissues	[307]
Ellagic acid inhibits E2-induced mammary tumorigenesis	Reverses the downregulation of miR-206		ACI model rat mammary tissue	[308]
Actin-like 6A (BAF53a), a subunit of the SWI/SNF chromatin remodeling complex	Elevated BAF53a	Downregulation of miR-206	Primary rhabdomyosarcoma tumors	[309]
Actin-like 6A (BAF53a)	BAF53a transcript is significantly higher in primary rhabdomyosarcomas than in normal muscle	Restoration 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 Lef1	Exogenous upregulation of miR-206 expression	Inhibition of Wnt, Tbx3 and Lef1 activities	Estrogen receptor alpha (ER-α)-positive human breast cancer; developing mammary buds	[310]
ANXA2 and KRAS	Stimulation of KRAS activity then induces NFKB1 expression;	Downregulated miR-206 in PDAC	PDAC tissues and cell lines	[311]
Induces NFKB1	Increased KRAS results in stimulation of cytokines CXCR2, CXCL1, CCL2, as well as CSF2 (GM-CSF) and VEGFC	Increased cell cycle progression, cell proliferation, migration and invasion
Downregulated miR-1 and miR-133a
PNP	PNP upregulated	Reduced miR-1, -133a	Prostate cancer	[97]
TAGLN2	TAGLN2 upregulated	Reduced miR-1, -133a	RCC	[136]
TAGLN2 and PNP	TAGLN2 and PNP upregulated	Reduced miR-1, -133a	MSSCC	[137]
PTMA and PNP	PTMA and PNP upregulated	Reduced miR-1, -133a	Bladder cancer (TCC)	[312]
LASP1	LASP1 upregulated	Reduced 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 expression	Inverse correlation with TAGLN2 levels	CpG islands upstream of miR-1-133a hypermethylated	Colorectal 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 cancer	miR-1 and mir-133b are significantly downregulated in recurrent prostate cancer tissue specimens	Recurrent prostate cancer tissue	[96]
Downregulated miR-1 and miR-206
NRF2 upregulated	Downregulated miR-1 and miR-206 expression	Upregulated expression of NRF2 induces increased expression HDAC4	Primary lung adenocarcinoma; DU145 human prostate cancer cell line	[99]
Loss of NRF2	Decreased 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 expression	A549 human NSCLC cell line	[99]
c-Met	c-Met upregulated	miR-1 and -206 downregulated	Human rhabdomyosarcoma	[89]
ARPC5 and GSTP1	ARPC5 and GSTP1 upregulated	Reduced miR-133a (and miR-206)	Lung SCC cell lines	[115]
Downregulated miR-133a and miR-133b
PKM2	PKM2 upregulated	Downregulated miR-133a, -133b	TSCC	[111]
FSCN1	FSCN1 upregulated	Downregulated miR-133a, -133b, (miR-145)	ESCC	[132]
		miR-133a, miR-133b downregulated	ESCC	[94]
KRT7	KRT7 upregulated	Downregulated (miR-133a and miR-133b)	Bladder cancer (TCC) and in vitro in BC KK47 cells	[315]
Downregulated miR-1, miR-206 and miR-133
myomiRs	Patient to patient variation in the up or down regulation of miR expression in both tumor and matched normal tissues	In 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 RCC	Each of miR-206, miR-1, miR-133b strongly downregulated	Restored expression strongly inhibited cancer cell proliferation,	RCC	[316]
Shorter overall survival and disease-free survival	Correlated with increased downregulated of miR-133b and/or miR-206	Both miR-133b and miR-206 significantly downregulated	Osteosarcoma tissues	[317]
Cell invasion and metastasis	miR-1, miR-133a, miR-133b downregulated	miR-133a, miR-133b involved in invasion and metastasis	ESCC	[94]

UPR: Unfolded protein response; PAKs: P21-activated kinases; EDN1: Endothelin 1; AKT1: V-akt murine thymoma viral oncogene homolog 1; HCC: Hepatocellular carcinoma; API5: Apoptosis inhibitor 5; LASP1: LIM and SH3 domain protein 1; XPO6: Exportin-6; CLCN3: Chloride channel, voltage-sensitive 3; G6PD: Glucose-6-phosphate dehydrogenase; BRCA1: Breast cancer 1, early onset; MCM7: Minichromosome maintenance complex component 7; PTMA: Prothymosin alpha; TWF1: Twinfilin actin-binding protein 1; CXCR4: Chemokine (C-X-C motif) receptor 4; HDAC4: Histone deacetylase 4; ANXA2: Annexin A2; SRSF9/SRp30c: Splicing factor serine/arginine-rich 9; ARPC5: Actin-related protein 2/3 complex subunit 5; GSTP1: Glutathione S-transferase pi 1; FSCN1: Fascin homolog 1; FTL: Ferritin light chain; BCL2L2: B-cell CLL/lymphoma 2-like 2; EGFR: Epidermal growth factor receptor; PNP: Purine nucleoside phosphorylase; PKM2: Pyruvate kinase, muscle type M2; KRT7: Keratin 7.

Table 5 Targets and pathways influenced by the upregulated myomiRs in different cancers

Factor(s)	Regulation	Regulator	Tissue/cell	Ref.
Upregulated miR-133b
Activated p-ERK, pAKT1 cause in vitro proliferation of cervical cancer cell lines, and promote in vivo tumorigenesis and metastasis	Downregulation of MST2, CDC42, RHOA	Upregulated miR-133b	Human cervical carcinoma tissue compared to surrounding normal cervical tissue	[121]
Decreased patient survival		Upregulated miR-133b	Progression bladder cancer	[122]
Androgen receptor	miR-133b directly represses CDC2L5, PTPRK, RB1CC1, CPNE3	miR-133b directly upregulated by AR	Hormone-sensitive human prostate cancer (LNCaP) cells stimulated by androgen	[123]
Activativated neuroendocrine neoplasia proliferation	Mutation in von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase gene (VHL)	Upregulated miR-133b expression in VHL- deficient pheochromocytoma	Human pheochromocytoma (PCCs) and paraganglioma (PGLs) neuroendocrine neoplasias	[318]
Upregulated miR-206
Cell reprogramming factor KLF4	KLF4 downregulated in colon cancer tissue, associated with increased miR-206	miR-206 strongly upregulated in colon cancer tissues	Human colon cancer tissue	[116]
Upregulated miR-1 and miR-133
Decreased survival of R172 IDH2-mutated subset of CN-AML patients, increases resistance to chemotherapy	Distinctive gene and microRNA expression profiles accurately predicted R172 IDH2 mutations	Upregulated expression of miR-1 and miR-133	De novo CN-AML patient bone marrow and blood samples	[151]
EVI1 increases aggressive cancer growth	EVI1 expression upregulated in established patient samples	Upregulated expression of miR-1-2 and miR-133-a-1	EVI1 expressing AML subset of patients	[120]
	ChIP assays show EVI1 binds to miR-1-2 gene promoter directly
CCND2	miR-1 and miR-133a were specifically overexpressed in the cases with t(14;16) translocation, correlates with down-regulated CCND2 expression	Upregulated miR-1 and miR-133-a	Multiple myeloma	[152]
Secreted myomiRs
miRs selectively released into serum (within exosome microparticles)	miR-1, miR-133a, and miR-133b selectively released		Human breast cancer	[319]
Circulating microRNA	Tumor-derived exosomes		Human non-small-cell lung cancer	[320]

AKT1: V-akt murine thymoma viral oncogene homolog 1; CN-AML: Cytogenetically normal acute myeloid leukemia.

Table 6 Validated myomiR targets related to cancer progression

Up regulated cell factor		Down regulated cell factor	Cancer type	Ref.
Downregulated myomiRs
Downregulated miR-1
	Mediator complex subunit 1 (Med1) and 31 (Med31) upregulated	miR-1 downregulated	Osteosarcoma	[257]
	Slug expression upregulated; enhanced cell migratory and invasive activities	miR-1 downregulated	Chordoma	[261]
	Slug expression upregulated; stimulation of EMT process	miR-1 reduced increasingly with cancer progression	Prostate adenocarcinoma	[321]
Downregulated miR-133a
	ARPC5 upregulated;	Downregulated miR-133a (> miR-206)	Lung SCC	[115]
			HNSCC	[272]
	CAV1 upregulated;	miR-133a downregulated	HNSCC	[322]
	Moesin upregulated;	miR-133a downregulated	HNSCC	[143]
	FSCN1 upregulated;	miR-133a/ miR-133b downregulated	ESCC	[132]
			Bladder cancer (TCC)	[274]
	GSTP1 upregulated;	miR-133a downregulated	HNSCC	[323]
			Bladder cancer (TCC)	[144]
			Lung SCC	[115]
	LASP1 upregulated;	miR-133a downregulated in 83% of colorectal tumors	Colorectal 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 downregulated	Bladder cancer (TCC)	[313]
	PKM2 upregulated;	miR-133a downregulated	TSCC	[111]
	Moesin upregulated;	miR-133a downregulated	HNSCC	[143]
	EGFR upregulated;	miR-133 downregulated	Hormone-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 downregulated	ESCC	[326]
	Reduced miR-133a expression correlated significantly with advanced clinical stages, poor histological differentiation and lymph node metastasis	Marked downregulation of miR-133a in primary EOC tumors and OVCAR-3 cell line	Epithelial ovarian cancer (EOC), and in OVCAR-3 cell line	[327]
Downregulated miR-133b
	FSCN1 upregulated;	miR-133a/-133b downregulated	ESCC	[132]
	FSCN1 mRNA upregulated;	miR-133b downregulated	Progressive GIST	[281]
	BCL2L2 upregulated;	miR-133b downregulated	Lung cancer	[85]
	MCL1 upregulated;	miR-133b downregulated	Lung cancer	[85]
	MET upregulated;	miR-133b downregulated	Colorectal cancer	[87]
	MET protein upregulated;	miR-133b downregulated	high grade osteosarcoma tumor samples and cell lines	[328]
	EGFR upregulated;	miR-133b downregulated	NSCLC	[105]
	Multiple cell factors elevated;	miR-133b downregulated	Prostate cancer	[282]
	FGFR1 downregulated;	miR-133b downregulated	Gastric cancer	[329]
	Gli1 protein downregulated by miR133b, Gli1 target genes, OPN and Zeb2, are indirectly regulated	miR-133b downregulated	Gastric cancer	[283]
	TAp63 supresses metastasis; downregulation target of miR-133b	miR-133b is a transcription target of TAp63, downregulated	Colon cancer cells	[330]
	Chemokine (C-X-C motif) receptor 4 protein downregulated by miR133b; upregulated in advanced cancer	miR-133b downregulated	CRC	[331]
	TBP-like 1 mRNA and protein are upregulated in CRC	miR-133b downregulated in CRC	CRC	[332]
Strong additional down regulation of miR-133b aids liver metastatic niche for CRC cells	miR-133b downregulated 3 × (significant) in liver metastasis compared to primary CRC	miR-133b downregulated in primary CRC compared to surrounding tissue	Metastatic 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 D1	miR-133a and -133b downregulated	Gastric cancer	[334]
	miR-133b target MMP-9 is upregulated	miR-133b downregulated	RCC	[335]
Downregulated miR-206
	ERα	ERα downregulates miR-206	ERα-positive breast cancer;	[294]
		miR-206 downregulated	Double feedback loop	[109]
		miR-206 downregulated		[293,336]
	ERα	miR-206 downregulated	EEC tissue	[110]
	SRC-1, SRC-3 and GATA-3 proteins contribute to estrogenic signalling	miR-206 downregulated	ERα-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 translation	Breast cancer cells and normal cells	[108]
	FGBP1	miR-206 gene double knockdown	miR-206-/- mouse skeletal muscle.	[12]
	VEGF upregulated	miR-206 downregulated	Laryngeal SCC cells	[113]
	VEGF upregulated	miR-206 downregulated	CRC tumors compared to matched normal tissue; (1DS assay)	[337]
	miR-206 correlates with negative ER status, negative PR status, and negative HER-2 status	Downregulated miR-206	Breast cancer tumor tissue	[338]
	miR-206 was downregulated in clinical TNBC tumor samples, one of its targets, actin-binding protein coronin was upregulated	Downregulated miR-206 associates with increased metastasis potential in breast cancers	High metastatic capacity TNBC tumors	[305]
Downregulated miR-1 and miR-133a
	PNP upregulated	miR-1/miR-133a downregulated	MSSCC	[137]
			Prostate cancer	[97]
			Bladder cancer (TCC)	[312]
	TAGLN2 upregulated;	miR-1/miR-133a downregulated	MSSCC;	[137]
			RCC	[138]
			HNSCC	[339]
			Bladder cancer (TCC)	[93]
	PTMA upregulated	miR-1 and miR-133a downregulated	Bladder cancer (TCC)	[312]
Downregulated miR-1 and miR-206
	MET levels correlated inversely with miR-1/206 expression	miR-1/206 downregulated	Up-regulation of MET in rhabdomyosarcoma	[89,288]
	HGFR upregulated	miR-1/206 downregulated	Breast cancer cells	[289]
	G6PD; PGD; TKT; GPD2 upregulated	miR-1/206 downregulated	Primary lung adenocarcinoma	[99]
Upregulated myomiRs
Upregulated miR-133b
miR-133b	miR-133b strongly upregulated	MST1, CDC42, RHOA, and DUSP1 downregulated	Cervical carcinoma	[121]
miR-133b	miR-133b is directly upregulated by AR	miR-133b represses CDC2L5, PTPRK, RB1CC1, and CPNE3	PCa prostate cancer cell line	[123]
Upregulated miR-206
miR-206	Strongly upregulated miR-206	KLF4 downregulated	Human colon cancer tissue	[116]
Upregulated miR-1 and miR-133a
miR-1-2 and miR-133-a-1	Upregulated miR-1-2 and miR-133-a-1	EVI1 (transcriptional activator of miR-1 and miR-133b)	AML	[120,151]
miR-1 and miR-133-a	Upregulated miR-1 and miR-133-a	Downregulated CCND2	Multiple myeloma	[152]
Up-regulation of exogenous myomiR expression in cell lines
Reduced cell proliferation	Estrogen receptor alpha	Overexpression of miR-206 has an inhibitory effect on cell proliferation	ERα-positive breast cancer cells over expressing mir-206	[289]
miR-133b	GSTP1 downregulated	Transgenic miR-133b overexpression	HeLa cervical cancer cells	[282]
miR-133b	FAIM downregulated	Transgenic miR-133b overexpression	HeLa cervical cancer cells	[282]
Apoptosis increased	TNFα-induced cell death is activated	Transgenic miR-133b overexpression	HeLa cervical cancer cells	[282]
Increased cell proliferation and migration	Downregulation of MST2	Transgenic miR-133b overexpression	CaSki cervical cancer cells	[121]
	Downregulation of CDC42
	Downregulation of RHOA
Increased cell proliferation and migration	Indirect upregulation of p-AKT1 activity	Transgenic miR-133b overexpression	CaSki cervical cancer cells	[121]
	Indirect upregulation of p-ERK activity
RB1CC1 downregulated	Exogenous upregulation of miR-133b;	miR-133bm promotes cell apoptosis, but suppressed cell proliferation and cell-cycle progression in aggressive PC-3 cells	PC3 prostate cancer cell line	[106]
	miR-133b directly targets RB1CC1 in LNCaP cells	In contrast in low-aggression LNCaP cells, miR-133b stimulate cell proliferation and cell-cycle progression, but inhibit apoptosis	Hormone sensitive prostate cancer LNCaP cell line
Cell proliferation decreased and apoptosis increased	Met, Twf1 and Ets1 and Bag4 activities downregulated	miR-1 expression is lower in mouse cSCCs compared to normal skin	Mouse cutaneous squamous cell carcinomas (cSCCs); A5 and B9 cSCCcell lines	[256]
		Transgenic miR-1 overexpression
Ets1 proto-oncogene	Repression of Ets1 expression inhibited HepG2 cell invasion and migration	Transgenic miR-1 overexpression	HCC HepG2 cells	[340]
lncRNA UCA1	Knockdown of lnc UCA1 expression phenocopied the effects of upregulation of hsa-miR-1	hsa-miR-1 decreased the expression of lnc UCA1 in bladder cancer cells in an Ago2-slicer-dependent manner	Human bladder cancer (TCC) cells	[156]
NOTCH3 signalling	miR-206 had a direct inhibition of NOTCH3 signalling and indirect interaction with other signalling pathways via CDH2 and MMP-9	miR-206 upregulation blocks the cell cycle, inhibits cancer cell proliferation and migration and activates cell apoptosis	SW480 (plus its metastatic strain) and SW620 colon cancer cell lines	[341]
FSCN1	miR-133b targets FSCN1 in GC cells; the direct knockdown of FSCN1 can also inhibit GC cell growth and invasion	Up regulation of miR-133b in GC cells inhibits cell proliferation, cell migration and invasion	miR-133b is significantly downregulated in GC tissues compared with adjacent normal tissues, as well as in GC cell lines	[342]
FSCN1	miR-133a targets FSCN1 in CRC cells;	Up regulation of miR-133a expression and downregulation of FSCN1 protein expression both suppress colorectal cancer cell invasion	miR-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

¹DS: Deep sequencing. HNSCC: Head and neck squamous cell carcinoma; ESCC: Esophageal squamous cell carcinoma; ARPC5: Actin-related protein2/3 complex, subunit 5, 16 kDa; CAV1: Caveolin-1; FSCN1: Fascin homolog 1; GSTP1: Glutathione S-transferase pi 1; TSCC: Tongue squamous cell carcinoma; EGFR: Epidermal growth factor receptor; TAp63: Tumor protein p63; CRC: Colorectal cancer; KLF4: Kruppel-like factor 4; SRC-1 and SRC-3: Steroid receptor coactivator proteins; HGFR: Hepatocyte growth factor receptor; G6PD: Glucose-6-phosphate dehydrogenase; PGD: 6-Phosphogluconate dehydrogenase; TKT: Transketolase; GPD2: Glycerol-3-phosphate dehydrogenase; RHOA: Ras homolog family member A; AML: Acute myeloid leukaemia; EVI1: Ecotropic virus integration site 1 transcription factor; MST2: Mammalian sterile 20-like kinase 2; RB1CC1: RB1 inducible coiled-coil 1; UCA1: Urothelial cancer associated 1; GC: Gastric cancer.