Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma

Table 1 Hepatic cancer stem cell markers and their roles in hepatocellular carcinoma recurrence

Markers	Biological functions in LCSCs	Signaling pathways	Recurrence	Ref.
CD133	Tumor angiogenesis, growth, self-renewal, invasion, and chemoresistance	AKT/PKB, IL-8/CXCL1, Notch	High recurrence	[16-23]
CD90	Preferably in poorly differentiated HCC, inflammation, circulation, drug resistance, and lipid metabolism	TGF-β/Smad	A shorter time to recurrence	[25-28]
CD44	Extensive proliferation, self-renewal, invasion, and tunorigenicity	TGF-β, AKT/GSK-3β/β-catenin, AKT/ERK/CXCR4	The significant risk factors of recurrence	[30-36]
CD24	Cell surface glycoprotein, drives CSC genesis	Stat3/Notch	A prognostic predictor for recurrence-free survival	[37-41]
CD13	Tumorigenicity, cell proliferation, cell cycle, self-renewal, and chemoresistance	ERK1/2	Early recurrence	[42-44]
CD47	Tumor initiation, self-renewal, and metastasis	CTSS/PAR2, NF-κB, IL-6	Shorter recurrence-free survival	[45-47]
OV6	Invasive and metastatic potential, form tumors, invasiveness, metastasis, substantial chemoresistance	Wnt/β-catenin, CXCL12/CXCR4/β-catenin		[48,49]
EpCAM	An early biomarker for HCC, self-renewal, differentiation, chemoresistance, highly invasion and tumorigenisis	Wnt/β-catenin	High recurrence	[50-54]

HCC: Hepatocellular carcinoma; CSC: Cancer stem cell; LCSCs: Liver cancer stem cells.

Table 2 The regulatory roles of miRNAs in hepatocellular carcinoma

miRNA	Target genes/pathways	Effects	Expression	Clinical relevance	Ref.
miR-9-3p	HBGF5, lncRNA SAMMSON, ERK1/2 pathway	Cell proliferation, migration, and invasion	Down	Lower levels in HCC than in healthy donors	[66]
miR-21	KLF5, CAMSAP1, DDX1, MARCKSL1, PTEN, AKT, D24 RECK, PDCD4, TETs/PTENp1/PTEN pathway, TGF-β1/smad3 pathway	Cell proliferation, migration, invasion, and metastasis	Up	Higher in HCC than in CHB and in healthy volunteers, early diagnosis	[55-58]
miR-26	ULK1, EphA2, TAK1, TAB3, NF-κB pathway	Apoptosis	Down	Poor survival	[67-69]
miR-30a	Beclin1, Atg5, Snail1, FOXA1, ADAMTS14, Ras/Raf/MEK/ERK pathway	Proliferation, apoptosis, metastasis, migration, invasion, and EMT	Down	Prevention of HCC recurrence	[70-73]
miR-122	ADAM10, ADAM17, IGF1R, SRF, SNAI1, SNAI2, WNT1, CREB1, BCL9, Cyclin G1, NMPDK4, LDHA, and CD133, Wnt/β-catenin pathway, IGF-1R pathway	Cell growth, proliferation, differentiation, metabolism, invasion, and EMT	Down	More sensitive to chemotherapeutic agents and improves the anti-tumor effect of sorafenib on HCC in vivo	[74-78]
miR-125b	MCL1, BCLw, IL-6R, SIRT7, SMAD2, SMAD4	Proliferation, metastasis, migration, and apoptosis	Down	A significantly longer time to recurrence and longer overall survival time	[79-82]
miR-130b-3p	HOXA5		Up	Poor prognosis, higher in patients with recurrence	[59]
miR-142	TGFβ, THBS4, LDHA, CD-133, HMGB1	Cell growth, metastasis, migration, and invasion	Down		[83-85]
miR-155	ZHX2, TP53INP1, TGF-β1 pathway	Cell proliferation, migration, invasion, and EMT	Up	Diagnostic biomarkers for HCC	[62, 62]
miR-182-5p	FOXO3, AKT, Wnt/β-catenin	Proliferation, motility, invasion, and metastasis	Up	Poor prognosis and early recurrence	[63]
miR-199b-5p	TGFβ, MAP4K3, DDR1	Metastasis, migration, invasion, and EMT	Down		[86, 87]
miR-200a	GAB1, FOXA2	Proliferation, invasion, migration, and EMT	Down	Biomarkers for early-stage HCC	[87, 89]
miR-203	Ki67, CAPNS1	Proliferation, invasion, migration, and metastasis	Down	Tumor recurrence and poor survival of patients with early-stage HCC	[90, 91]
miR-221	p53, PUMA, NF-kB, STAT3, AAV8, PTEN, TIMP3, TRAIL, RAS/RAF/ERK, AKT	Apoptosis, and proliferation	Up		[64, 65]
miR-449a	Notch1, FOS, Met, Calpain6, POU2F1, Notch pathway	Metastasis, apoptosis, proliferation, migration, invasion, and EMT	Down	Short-term recurrence	[92-94]
miR-541	ATG2A, RAB1B	Inhibited the growth, metastasis, and autophagy	Down	Associated with malignant clinicopathologic phenotypes, recurrence and survival	[95]

HCC: Hepatocellular carcinoma; EMT: Epithelial mesenchymal transition.