Hepatocellular carcinoma viral etiology and molecular mechanisms
Author
Yıldız, Esra
Advisor
Öztürk, Mehmet
Date
2003Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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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.