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Malignant transformation and EGFR activation of immortalized mouse liver epithelial cells caused by HBV enhancer‐X from a human hepatocellular carcinoma

We have previously observed that all human hepatocellular carcinomas (HCCs) from HBV carriers examined had the integrated X region. In this study, HBV DNA was isolated from an integration site in one HCC that had a single, very small integrated viral DNA including the X region, but it had no expression of X gene as poly(A)RNA. It was found that HBV DNA was present between alphoid repetitive sequences, and it included Enhancer and X regions, encompassing the adr sequence from 910 to 1811. Nucleotides for 8 amino acids at the 3’ end, a stop codon of X gene and a poly(A) signal downstream of X gene were lost by integration, and nucleotides for 7 amino acids and a stop codon were substituted by a connected alphoid sequence. When this cloned HBV DNA was transfected with an expression vector to an immortalized mouse liver epithelial cell line, MLE‐10, malignant transformation occurred. Transformants having expressed poly(A)RNA of the X gene showed anchorage‐independent growth in soft agar and tumor formation in the subcutis of nude mice. The mRNA level of EGFR was found to be remarkably enhanced in X‐transformed cells, in contrast with the absence of this mRNA in parental and ras‐transformed MLE‐10. Our data provide evidence that the Enhancer‐X region alone is the key contributor to the malignant change of pre‐malignant liver cells in HBV carriers through activation of some specific genes, such as EGFR. Int. J. Cancer 85:518–522, 2000. © 2000 Wiley‐Liss, Inc.