TRANSACTIVATION OF CELLULAR GENE-EXPRESSION BY HEPATITIS-B VIRAL-PROTEINS - A POSSIBLE MOLECULAR MECHANISM OF HEPATOCARCINOGENESIS

Epidemiologic data indicate the crucial role of chronic hepatitis B vi rus (HBV) infection in hepatocellular carcinoma (HCC) development. On the molecular level, HBV sequences are frequently integrated in hepato cellular DNA. However, in contrast to the woodchuck model, in which sp ecific HBV-DNA integration is detectable in most cases, insertional (i n-) activation of cellular genes seems to be a rare event in man. The recent discovery of transactivating functions: exerted by HBx and trun cated HBs(urface) proteins supports the notion thar transactivation of cellular gene expression could. be relevant to hepatocarcinogenesis. HBV transactivator sequences are present in 81% (21/26) of HCC tissues or hepatoma-derived cell lines, At least one transactivator protein w as functional in all cases investigated so far, The 16.5-kDa HBx trans activator has been shown to stimulate gene expression from various cel lular target sequences, In vitro, HBx displays oncogenic potential, A second type of transactivator is encoded in the preS/S region of HBV. In contrast to HBx, HBs transactivators require carboxyterminal trunca tion to gain their transactivating function. Unlike full-length M(iddl e)HBs, the truncated MHBs(t) is retained in the endoplasmic reticulum and not secreted into the surrounding medium. Cellular gene expression is stimulated by regulatory elements of the human prato-oncogenes c-f os and c-myc, as well as by the hepatic acute-phase interleukin-6 gene , Synthetic binding sites for the transcription factors NF-kappa B, AP -1, AP-2, SRE, and Spl render minimal promoters activatable. NF-kappa B-mediated transactivation by MHBs(t) can be suppressed by radical sca venging antioxidants, indirectly suggesting that reactive oxygen inter mediates are involved. In summary, the data provide indirect evidence that the transactivating effects of HBV proteins may contribute to the multistep pathogenesis of HCC. (C) Journal of Hepatology.