The impact of growth modulation of liver carcinogenesis

生长调节对肝癌发生的影响

• 批准号: 7627384
• 负责人: XIAO-MING YIN
• 金额: $ 17.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627384
• 关键词: Affect; Alcoholic Liver Diseases; Apoptosis; Arts; Biological; C57BL/6 Mouse; Calcium; Carcinogens; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Proliferation; Cell Proliferation Regulation; Cells; Cessation of life; Chemicals; Chronic; Cyclin E; Development; Diagnostic Neoplasm Staging; Diethylnitrosamine; Endoplasmic Reticulum; Event; Exposure to; Future; Gene Deletion; Genetic; Goals; Growth; Hepatocarcinogenesis; Hepatocyte; Homeostasis; Investigation; Lesion; Liver; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Mus; Natural History; Neonatal; Outcome; Primary carcinoma of the liver cells; Process; Protein Family; Regulation; Role; Staging; System; Testing; Therapeutic; Time; Transgenic Organisms; Tumor Burden; Tumor Expansion; Tumor stage; Viral hepatitis; Work; base; carcinogenesis; chemical carcinogen; chemical carcinogenesis; genetic element; innovation; liver cell proliferation; neoplastic; novel; response; tool; tumor; tumor initiation; tumorigenesis

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.

描述（由申请人提供）：肝细胞癌（HCC）是许多慢性肝病（例如病毒性肝炎和酒精性肝病）以及接触化学致癌物的常见终末期结果。肝癌的发生发展是一个缓慢的过程，涉及起始、促进、进展等多个阶段，周期较长。控制该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致癌模型中，我们发现Bid（一种促死亡Bcl-2家族蛋白）的缺失，矛盾地抑制了从微病灶发展的早期阶段开始的致癌作用，此时肝细胞增殖的能力至关重要。这种早期效应对二乙基亚硝胺给药后 8-12 个月检查的总体肿瘤发展有显着影响。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。我们假设Bid通过促进细胞增殖来促进肿瘤发生的启动，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检验这一假设：1）检查 Bid 在 DEN 诱导的肝肿瘤范例中以及在不同遗传背景的小鼠中的影响，这些小鼠已知会影响肿瘤的发生和细胞增殖能力； 2) 使用诱导转基因和基因缺失模型，根据 Bid 在细胞增殖和细胞死亡中的功能，确定 Bid 对肿瘤发展的阶段特异性影响； 3）探讨Bid通过影响内质网钙稳态来调节细胞周期进程的机制。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作用，特别是在肝脏系统中，以及这种潜力如何受到不同遗传元件的调节。