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

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.