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Abstract
Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). To determine if HBV integration occurs and affects cellular genes at such a stage of infection, we analysed viral-host junctions in chronic hepatitis tissues without HCC using PCR amplification with primers specific to human Alu-repeat and HBV. We obtained 42 independent viral-host junctions from six patients examined and identified chromosomal locations for 20 of the 42 junctions. In six clones, each integration apparently affected a single gene. These six candidate genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. Our data, together with previously reported HBV integrants in HCCs, suggested preferential HBV integration into chromosome 3 (P = 0.022). Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and potentially involved in early steps of the process leading to carcinogenesis.
Highlights
Epidemiologic data provide compelling evidence (Beasley et al, 1981; Yu et al, 2000) for a role of hepatitis B virus (HBV) in the development of hepatocellular carcinoma (HCC)
PCR products were inserted into a plasmid vector, a total of 160 clones that hybridized to an HBV probe were selected and their nucleic acid sequences were determined
HBV-Alu PCR because of its advantage in amplifying viral–host junctions that coexist with free viral sequences
Summary
Epidemiologic data provide compelling evidence (Beasley et al, 1981; Yu et al, 2000) for a role of hepatitis B virus (HBV) in the development of hepatocellular carcinoma (HCC). 2005; published online 4 April 2005 istic lifecycle that includes integration into the host genome (Bréchot et al, 2000). One complication is that human tumorigenesis is a multistep process and several viral mechanisms are possibly involved in each step, including cis- and transactivation of cellular genes by viral proteins, antiapoptotic action, induction of genomic instability and insertional mutagenesis (Nevins and Vogt, 1996). Several groups have independently reported HBV integration into the human telomerase reverse transcriptase (hTERT) gene in HCCs, as well as in hepatoma derived cell lines, proving that viral insertion activates hTERT expression and, possibly, maintenance of telomere length (Gozuacik et al, 2001; Horikawa and Barrett, 2001; Ferber et al, 2003a).
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