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

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.