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Mutant p53 but not Hepatitis B Virus X Protein Is Present in Hepatitis B Virus-related Human Hepatocellular Carcinoma¹

Departments of Virology [F. H., N. W., R. K.] and Histopathology [M. H. C. G., M. R. A.], Royal Postgraduate Medical School, Ducane Road, London W12 ONN, United Kingdom

Hepatitis B virus (HBV) X protein is thought to play an important role in the development of hepatocellular carcinoma. Recent studies on a transgenic mouse tumor model suggest that HBV X protein may contribute to transformation by binding to and inactivating the cellular growth suppressor protein p53. We have studied 31 hepatocellular carcinoma tissues from Chinese patients for the possible occurrence of such interactions. Although most of the samples contained markers of HBV infection, including free and/or integrated HBV DNA, there was no detectable expression of HBV X protein by Western blot, immunoprecipitation, or histochemical staining. There was also no evidence of HBV X protein associated with p53 immunoprecipitated from the tumors. These observations suggest that, in naturally occurring human hepatocellular carcinoma, such interactions are uncommon and, therefore, unlikely to be of relevance in the latter stages of tumor development. On the other hand, 29 of 31 (93%) samples contained mutated forms of p53, as determined by various antibodies that detect wild-type or mutant p53 or both, and by the association of heat shock protein 70 with immunoprecipitated p53. These results show that conformationally altered p53 protein is present in tumors at a much higher frequency than is suggested by the presence of known mutations in the gene. This mutant p53 is functionally inactive, as suggested by the lack of expression of the p53-induced M_r 21,000 Cip1/Waf1 protein in the tumors. Because this inactivation of p53 was not correlated with the expression of HBV X protein, any interaction of HBV X protein with p53 may be relevant only during acute infection. Such an interaction could serve to relax cell growth control at a time when virus replication requires hepatocyte destruction to be balanced by regeneration.

¹ This study was supported by Cancer Research Campaign, Great Britain, Grant SP2179/0101 (R. K.), F. H. is the recipient of a scholarship from the Gottlieb Daimler and Karl Benz Foundation (Ladenburg, Germany).

² To whom requests for reprints should be addressed. Phone: 44-181-740-3329; Fax: 44-181-743-8331; E-mail: rkoshy@rpms.ac.uk.

Received 7/27/95. Accepted 10/ 9/95.

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