TRANSACTIVATION OF TRANSFORMING-GROWTH-FACTOR ALPHA-GENE BY HEPATITIS-B VIRUS PRES1

Hepatitis B virus (HBV) causes acute and chronic liver injury, and int egration of HBV DNA is considered to be an important pathogenic determ inant for hepatocarcinogenesis and tumor development. Transforming gro wth factor cu (TGF-alpha) drastically accelerates hepatocarcinogenesis when it is overexpressed in TGF-alpha transgenic mice (C. Jhappan et al, Cell, 61: 1137-1136, 1990). In HBV-infected patients, hepatocellul ar carcinoma (HCC) cells show elevated expression of TGF-alpha (C. C. Hsia et al, J. Med. Virol., 43: 216-221, 1994), the mechanism for whic h, however, has not been clarified get. We here show that preS1, a par t of the HBV large surface protein, carries a transcriptional transact ivation domain and activates the transcription of the TGF-alpha gene b y 2-fold in human HCC HuH6 cells. The responsive elements are restrict ed to the 315-bp segment of the proximal TGF-alpha promoter (-373 to - 59). Furthermore, the expression of TGF-alpha was markedly increased i n permanently preS1-producing HuH6 transformants. The crucial role for HBV preS1 in hepatocarcinogenesis and tumor development through trans activation of the TGF-alpha gene may give us new insight into the unde rstanding of pathogenesis and therapy of viral hepatocarcinogenesis.