Role of microRNAs in hepatocellular carcinoma: a clinical perspective

Figures & data

Figure 1 Predicted effects of deregulated miRNAs in hepatocarcinogenesis. miR-122, miR-199, miR-221 and miR-21 were shown by various studies to be consistently deregulated in HCC. Via aberrant control of protein-coding gene targets (only the major ones are shown), their deregulation is expected to induce biomolecular effects that promote tumorigenesis

Abbreviations: miRNA, microRNA; HCC, hepatocellular carcinoma.

Table 1 microRNAs with potential prognostic impact in patients with HCC

miRNAs	Molecular alteration	Clinical significance	Reference
20 miRNAs	Signature	Venous metastasis, overall survival	131
19 miRNAs	Signature	Poor survival	47
miR-19a, miR-886-5p, miR-126, miR-223, miR-24 and miR-147	Signature	Predictor of overall survival and recurrence-free survival after LT	132
miR-26a	Downregulation	Poor survival	133
miR-122	Downregulation	Gain of metastatic properties	39,40
miR-122	Downregulation	Early recurrence	38
Let-7 members	Downregulation	Early recurrence	134
miR-199a-3p	Downregulation	Reduced time to recurrence	49
miR-199b-5p	Downregulation	Poor overall survival and progression-free survival rates	51
miR-101	Downregulation	Advanced tumor progression, poor prognosis	135
miR-125a	Upregulation	Better survival	136
miR-92, miR-20, miR-18	Upregulation	Poor differentiation	46
miR-372	Upregulation	Advanced TNM stage	137
miR-221	Upregulation	Multinodularity, reduced time to recurrence	59
miR-221	Upregulation	Gain of metastatic properties	138
miR-221	Upregulation	High tumor capsular infiltration	139
miR-17-5p	Upregulation	Multiple tumor nodules, vein invasion, shortened overall survival	140
miR-155	Upregulation	High recurrence and poor prognosis following OLT	141
miR-203	Upregulation	Good prognosis	142
miR-18	Upregulation	Poor prognosis	143

Abbreviations: HCC, hepatocellular carcinoma; miRNAs, microRNAs; TNM, tumor-node-metastasis; LT, liver transplantation; OLT, orthotopic liver transplantation.

Note: Data adapted from Negrini et al.³⁰

Table 2 Circulating microRNAs in liver disease

miRNAs	Sample	Clinical condition	Clinical relevance	Reference
miR-122	Serum	High levels in patients with HCC or chronic hepatitis; lower levels in severe stages of fibrosis	Biomarker for liver injury but not specific for HCC; indicator of fibrosis progression in CHC infection; marker to distinguish patients with CHC from healthy controls	74,76,77, 144,145
miR-21	Serum/plasma	High levels in patients with HCC or chronic hepatitis; higher levels in patients with HCC than in those with chronic hepatitis or healthy volunteers	Biomarker for liver injury but not specific for HCC; biochemical marker for HCC	73–75,146
miR-223	Serum	High levels in patients with HCC or chronic hepatitis	Biomarkers for liver injury but not specifically for HCC	73
miR-885-5p	Serum	High levels in patients with HCC, LC, or CHB	Complementary biomarker for detection and assessment of liver pathologies	147
miR-16 miR-34a	Serum	Higher levels in patients with NAFLD than in controls	Correlation with liver enzymes levels, fibrosis stage, and inflammation activity; biomarkers of diagnosis and histological disease severity in patients with CHC or NAFLD	74
miR-221	Serum	High levels correlated with tumor size, cirrhosis, and tumor stage	Predictive significance for prognosis of patients with HCC	146
miR-15b miR-130b	Serum	Higher levels in tumors during the exploration phase on resected tumor/adjacent and nontumor tissues; lower levels after surgery	Biomarker with clinical value for HCC screening	148
miR-20a miR-92a	Plasma/serum	High levels in HCV-infected patients with fibrosis compared with healthy volunteers or liver disease not associated with HCV; higher levels in acute and chronic HCV-infected patients as compared with healthy volunteers	Biomarkers for early detection of HCV infection; miR-20a is a predictive biomarker of HCV-mediated fibrosis	149

Abbreviations: HCC, hepatocellular carcinoma; CHC, chronic hepatitis C; CHB, chronic hepatitis B; LC, liver cirrhosis; NAFLD, nonalcoholic fatty liver disease; HCV, hepatitis C virus; miRNAs, microRNAs.

Figure 2 Therapeutic strategies based on modulation of miRNA activity. Summary of preclinical studies (on the left) based on miRNA inhibition, miRNA replacement, and conditionally replicating adenoviruses regulated by miRNA (microRNA) target elements. On the right are clinical trials ongoing using miRNA-based drugs.

Table 3 microRNAs and cancer stem cells in HCC

miRNAs	Regulatory role in liver cancer stem cells	Reference
miR-181	Maintenance of EpCAM + AFP + HCC cells by inhibiting hepatic cell differentiation and promoting HCC stemness through targeting the transcriptional regulators CDX2 and GATA6 as well as the Wnt signaling inhibitor, NLK	150,151
miR-193b	Regulation of proliferation, migration, and invasion potential of HCC cells by downregulation of ETS1	152
miR-130b	Promotion of tumor growth and self-renewal in CD133+ T-ICs by downregulation of TP53INP1	153
miR-122	Modulation of self-renewal of hESCs and HCC proliferation by suppressing translation of the metabolic protein PKM2	154
miR-145	Modulation of downstream stem cell-related gene target Oct4	155
miR-150	Self-renewal of CD133+ liver CSCs through direct negative regulation of the downstream target, c-Myb	156
miR-200c	The miR-200-controlled epithelial-mesenchymal transition is functionally important for the development of stem-like cells associated with poor prognosis	157
miR-216a; miR-216a/217	Overexpression of these miRNAs activates the PI3K/Akt and TGF-β pathways by targeting PTEN and SMAD7, contributing to neoplastic transformation of LPCs to hepatic T-ICs, facilitating hepatocarcinogenesis and tumor recurrence in HCC	158,159
miR-214	Silencing of miR-214 modulates expression of EZH2, CTNNB1, and CDH1, increasing EpCAM+stem-like cells	160

Abbreviations: HCC, hepatocellular carcinoma; EpCAM, epithelial cell adhesion molecule; AFP, alpha-fetoprotein; CDX2, caudal type homeobox transcription factor; GATA6, GATA binding protein 6; NLK, nemo-like kinase; T-ICs, tumor-initiating cells; PKM2, pyruvate kinase isozymes M1/M2; CSCs, cancer stem cells; TGF-β, transforming growth factor-beta; PTEN, phosphatase and tensin homolog deleted on chromosome 10; SMAD7, mothers against decapentaplegic homolog 7; LPCs, liver progenitor cells; EZH2, enhancer of zeste homolog 2; CTNNB1, β-catenin; CDH1, E-cadherin; miRNAs, microRNAs.

NegriniMGramantieriLSabbioniSCroceCMmicroRNA involvement in hepatocellular carcinomaAnticancer Agents Med Chem201111650052121554203

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