Hepatocellular carcinoma (HCC) is a frequent end-stage outcome of many chronic liver diseases, such as viral hepatitis and alcoholic liver disease, and of exposure to chemical carcinogens. The development of liver cancer is a slow process that involves multiple stages of initiation, promotion and progression, encompassing a long period. Molecular events controlling the process have not been fully elucidated, particularly at the early stage of tumor initiation. In a chemical hepatocarcinogenic model employing the classical carcinogen, diethylnitrosamine, we found that deletion of Bid, a pro-death Bcl-2 family protein, paradoxically suppressed the carcinogenesis starting at the early stage of microfoci development, when the capability of hepatocyte proliferation is critically involved. This early effect had a significant impact on overall tumor development examined 8-12 months after diethylnitrosamine administration. Further studies revealed a novel function of Bid in promotion of cell cycle entry and in regulation of intracellular calcium homeostasis. We hypothesize that Bid facilitates the initiation of tumorigenesis by promoting cell proliferation but also exert its pro-apoptosis function in the later stage of tumor development. We are proposing to test this hypothesis through the following approaches: 1) Examination of the effect of Bid in DEN-induced liver tumor paradigms and in mice of different genetic backgrounds that are known to affect the tumor initiation and cell proliferation capability; 2) Determination of the stage-specific effect of Bid on tumor development based on its function in cell proliferation and cell death using inducible transgenic and gene deletion models; 3) Exploration of the mechanisms of Bid in regulating cell cycle progression via its effects on calcium homeostasis in endoplasmic reticulum. We hope that these studies will allow us to achieve our long term goal of understanding how the growth potential of cells affects chemical carcinogenesis, particularly in the liver system, and how this potential is regulated by different genetic elements.
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