Hepatocellular carcinoma viral etiology and molecular mechanisms

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent carcinomas throughout the world, being responsible for more than 1 million deaths annually and has a strong association with several etiological factors including aflatoxinB1, alcohol and Hepatitis virus B and C. Several studies suggested that HCV subtype 1b causes more severe liver diseases including HCC in a high manner and resistance to antiviral therapy. So, it is important to know genotype and some characteristics of HCV which are unique for the countries to develop better strategies regarding public health. By using direct sequencing information from 5`UTR and NS5B regions we identified subtype 1b as a predominant hepatitis C virus genome in Turkey. Next, the full genome sequence of a Turkish 1b isolate (HCV-TR1) was obtained by cloning of polypeptide-encoding region into 7 overlapping fragments. Although major structural and functional motifs of HCV proteins were maintained in HCV-TR1, it displayed amino acid substitutions in 6 out of 9 major cytotoxic T-cell epitopes. Several HCV proteins have been reported to contribute hepatocellular malignancy by interaction with critical cellular proteins involved in hepatocyte proliferation and survavil. Such studies often use HCC-derived cell lines as experimental models. As a prerequisite to future studies about the Turkish HCV 1b isolate in term of its contribution to HCC developments we investigated on phenotypic characterization of HCC cell lines. We provide experimental evidence that α-fetoprotein-producing HCC lines display in vitro liver stem cell-like properties with self-renewing capability and multi-lineage differentiation potential, even after single-cell cloning. However, their ability to generate fully differentiated normal progeny was disrupted, even if they modulate their differentiation program in response to external factors. These features qualify AFP-producing HCCs as “mis-specified” liver stem cell cancers whose cellular programs are deviated from repopulating liver to forming malignant tumors. Interestingly, stem-like cells described here have been used extensively to study the role HCV proteins. Our observations offer new opportunities for addressing the potential role of HCV in the misspecification of liver stem cells in relation with viral hepatocellular carcinogenesis.