MicroRNA involvement in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Curative options for HCC are limited and exclusively available for patients carrying an early stage HCC. In advanced stages, traditional chemotherapy proved to be only marginally effective or even toxic. Thus, the identification of new treatment options is needed. New targets for non-conventional treatment will necessarily take advantage of progresses on the molecular pathogenesis of HCC. MicroRNAs (miRNAs) are a group of tiny RNAs with a fundamental role in the regulation of gene expression. Aberrant expression of several miRNAs was found to be involved in human hepatocarcinogenesis. miRNA expression signatures were correlated with bio-pathological and clinical features of HCC. In some cases, aberrantly expressed miRNAs could be linked to cancer-associated pathways, indicating a direct role in liver tumourigenesis. For example, up-regulation of mir-221 and mir-21 could promote cell cycle progression, reduce cell death and favour angiogenesis and invasion. These findings suggest that miRNAs could become novel molecular targets for HCC treatment. The demonstration of in vivo efficacy and safety of anti-miRNA compounds has opened the way to their use in clinical trials.

Figure 1

Schematic representation of pathways affected by miRNAs deregulated in human hepatocellular carcinoma. Receptor tyrosine kinase (here indicated HGF/MET axis solely), RAS and PI3K pathways affected by the down-regulated (downward green arrow) miR-1, miR-199a*, Let-7 and the up-regulated (upward red arrow) miR-21 may lead to cell growth, survival, motility, invasion and metastasis. The cell cycle progression is mainly affected by the miR-221 (and miR-222, not indicated) up-regulation, which can repress the CDK inhibitors CDKN1 B/p27 and CDKN1 C/p57.