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Transactivation of Transforming Growth Factor Gene by Hepatitis B Virus preS1

The First Department of Internal Medicine [M. O., T. S., S. O.] and Laboratory of Molecular Biology, Medical Research Center [K. M., J. N., K. O., T. T.], Kochi Medical School, Okoh, Nankoku Kochi 783-8505, Japan

Hepatitis B virus (HBV) causes acute and chronic liver injury, and integration of HBV DNA is considered to be an important pathogenic determinant for hepatocarcinogenesis and tumor development. Transforming growth factor (TGF-) drastically accelerates hepatocarcinogenesis when it is overexpressed in TGF- transgenic mice (C. Jhappan et al., Cell, 61: 1137–1146, 1990). In HBV-infected patients, hepatocellular carcinoma (HCC) cells show elevated expression of TGF- (C. C. Hsia et al., J. Med. Virol., 43: 216–221, 1994), the mechanism for which, however, has not been clarified yet. We here show that preS1, a part of the HBV large surface protein, carries a transcriptional transactivation domain and activates the transcription of the TGF- gene by 2-fold in human HCC HuH6 cells. The responsive elements are restricted to the 315-bp segment of the proximal TGF- promoter (-373 to -59). Furthermore, the expression of TGF- was markedly increased in permanently preS1-producing HuH6 transformants. The crucial role for HBV preS1 in hepatocarcinogenesis and tumor development through transactivation of the TGF- gene may give us new insight into the understanding of pathogenesis and therapy of viral hepatocarcinogenesis.

¹ To whom requests for reprints should be addressed, at The First Department of Medicine, Kochi Medical School, Okoh, Nankoku, Kochi 783-8505, Japan. Phone and Fax: 81(888)80-2338; E-Mail: onishis@med.kochi-ms.ac.jp.

Received 12/22/97. Accepted 3/19/98.

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