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Alteration of Gene Expression in Human Hepatocellular Carcinoma with Integrated Hepatitis B Virus DNA

Authors' Affiliations: Departments of ¹ Hepatology, ² Surgery, and ³ Nuclear Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan; ⁴ Bioinformatics Center, Institute for Chemical Research, Kyoto University, Kyoto, Japan; and ⁵ Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Requests for reprints: Akihiro Tamori, Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, 545-8585 Osaka, Japan. Phone: 81-6-6645-3811; Fax: 81-6-6646-1433; E-mail: atamori{at}med.osaka-cu.ac.jp.

Purpose: Integration of hepatitis B virus (HBV) DNA into the human genome is one of the most important steps in HBV-related carcinogenesis. This study attempted to find the link between HBV DNA, the adjoining cellular sequence, and altered gene expression in hepatocellular carcinoma (HCC) with integrated HBV DNA.

Experimental Design: We examined 15 cases of HCC infected with HBV by cassette ligation–mediated PCR. The human DNA adjacent to the integrated HBV DNA was sequenced. Protein coding sequences were searched for in the human sequence. In five cases with HBV DNA integration, from which good quality RNA was extracted, gene expression was examined by cDNA microarray analysis.

Results: The human DNA sequence successive to integrated HBV DNA was determined in the 15 HCCs. Eight protein-coding regions were involved: ras-responsive element binding protein 1, calmodulin 1, mixed lineage leukemia 2 (MLL2), FLJ333655, LOC220272, LOC255345, LOC220220, and LOC168991. The MLL2 gene was expressed in three cases with HBV DNA integrated into exon 3 of MLL2 and in one case with HBV DNA integrated into intron 3 of MLL2. Gene expression analysis suggested that two HCCs with HBV integrated into MLL2 had similar patterns of gene expression compared with three HCCs with HBV integrated into other loci of human chromosomes.

Conclusions: HBV DNA was integrated at random sites of human DNA, and the MLL2 gene was one of the targets for integration. Our results suggest that HBV DNA might modulate human genes near integration sites, followed by integration site–specific expression of such genes during hepatocarcinogenesis.

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