The impact of growth modulation of liver carcinogenesis

描述(由申请人提供)：肝细胞癌是许多慢性肝病的常见终末期结局，如病毒性肝炎和酒精性肝病，以及暴露于化学致癌物。肝癌的发展是一个缓慢的过程，涉及启动、促进和发展多个阶段，包括一个较长的时期。控制这一过程的分子事件尚未完全阐明，特别是在肿瘤发生的早期阶段。在使用经典致癌物二乙基亚硝胺的化学肝癌模型中，我们发现Bid，一个促死亡的Bcl2家族蛋白的缺失，矛盾地抑制了从微灶发展的早期开始的癌变，此时肝细胞的增殖能力是关键的。这一早期效应对服用二乙基亚硝胺8-12个月后观察到的总体肿瘤发展有显著影响。进一步的研究揭示了Bid在促进细胞周期进入和调节细胞内钙稳态方面的新功能。我们推测，Bid通过促进细胞增殖促进肿瘤发生，但也在肿瘤发展的后期发挥其促凋亡功能。我们建议通过以下方法来验证这一假说：1)检测BID在DEN诱导的肝癌模型中以及在不同遗传背景的小鼠中的作用，这些影响已知会影响肿瘤的起始和细胞增殖能力；2)根据BID在细胞增殖和细胞死亡中的功能，利用可诱导的转基因和基因缺失模型来确定BID在肿瘤发生中的阶段特异性作用；3)通过对内质网钙稳态的影响，探讨BID调节细胞周期进展的机制。我们希望这些研究将使我们能够实现我们的长期目标，即了解细胞的生长潜力如何影响化学致癌，特别是在肝脏系统中，以及这种潜力如何受到不同遗传因素的调节。

DESCRIPTION (provided by applicant): 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.