MiR–198 is under- and miR–122 is overexpressed in HCV-associated hepatocellular carcinomas

Aims: Several studies in recent years have shown that expression of micoRNAs (miRNAs) is deregulated in human malignancies. MiR–122 is a miRNA that constitutes 70% of total miRNA in the liver, modulates the expression of the Hepatitis C Virus RNA by interacting with the 5´ noncoding region of the viral genome and has been suggested to play a crucial role in hepatocarcinogenesis. Since the miRNA expression profile has been proposed to be an important molecular prognostic marker of carcinogenesis, we studied the expression pattern of the liver specific miR–122 and of miR–198, shown by a screening assay to be dysregulated in a small HCC cohort.

Methods: Expression of miR–198 and miR–122 was examined by real-time PCR in 52 hepatic nodules from 39 patients with Hepatitis C. Nine of these tumors were dysplastic nodules (3 low-grade, 6 high-grade) and 43 were hepatocellular carcinomas (8 well differentiated, 30 moderately differentiated, 5 poorly differentiated). The expression of miR–122 was also investigated in four matched cirrhotic tissue samples away from the tumors and in the hepatoma cell lines SK Hep–1, Hep 3B and HepG2.

Results and Discussion: MiR–198 was more than 6-fold downregulated while miR–122 was significantly upregulated in dysplastic nodules and hepatocellular carcinomas arising in Hepatitis C Virus infection compared to normal liver parenchyma and matched cirrhotic tissue. Metastases of the hepatocellular carcinomas to the lung or kidney did not show dysregulation. MiR–122 has in the past been proposed to function as a tumor suppressor by downregulating Cyclin G1. The upregulation of miR–122 in our HCV-infected population may derive from a selection of hepatoma cells that are able to circumvent tumorigenic repression. MiR–198 has not been reported to by downregulated in tumors before, is located within the 3´ UTR (untranslated region) of the gene for human follistatin related protein and targets an unknown mRNA.

Conclusions: Selected miRNAs are significantly dysregulated in HCV-associated hepatocellular carcinomas and may serve as possible future targets for novel therapies. Additional studies will aim to elucidate their mechanisms of function and exact targets.

Hepatitis C - hepatocellular carcinoma - microRNA - real-time PCR