GROWTH FACTORS AND LIVER TUMOR PROMOTION

描述(改编自研究人员摘要)：肝细胞 癌症是世界上最常见的恶性肿瘤之一，具有 肿瘤发病率接近每年每100,000人中有150人 中国。尽管美国的肝癌发病率较低 美国国家毒理学研究所确定的60%的化学物质 计划中的致癌物质会引起大鼠和小鼠的肝脏肿瘤。 有趣的是，其中一些制剂似乎通过肿瘤发挥作用。 促进而不是启动机制。因此，为了 适当评估外来生物制剂的高风险，它是 有必要确定肝肿瘤的分子事件 启动子促进肝细胞癌的形成。这个 研究人员有证据表明，通过 苯巴比妥(PB)是耐药细胞的自然选择过程 对PB产生的生长抑制环境。结果还包括 提示甘露糖6-磷酸/类胰岛素选择性增加 正常人M6P/IGFII受体和转化生长因子β的水平 肝细胞在建立有丝分裂抑制选择性中起重要作用 PB促进肝脏肿瘤形成所需的压力。两者都有 生长抑制因子--转化生长因子-β的激活和降解 有丝分裂原IGFII依赖于它们与M6P/IGFII受体的结合。 M6P/IGFII受体在小鼠体内印迹，并可能存在于一个亚群中 人类的生命。他们最近还发现了78%的损失 人肝细胞癌M6P/IGFII受体基因座杂合性缺失 这些发现有力地支持了这种受体的假设 在肝癌的发生中起到肿瘤抑制的作用。因此， 这项赠款申请的总体目标是确定 M6P/IGFII受体和转化生长因子β在肝癌发生中的作用 具体地说，他们建议：1)确定转录 M6P/IGFII受体调控元件的研究 基因表达；2)确定基因表达是否降低 肝肿瘤M6P/IGFII受体基因甲基化改变； 3)确定M6P/IGFII受体基因的杂合性缺失程度 人肝细胞癌中的基因定位取决于肿瘤的病因和分期 发展；4)确定肝癌剩余等位基因的突变和 M6P/IGFII受体基因座上的杂合性缺失；以及5)使用转基因技术确定 小鼠是否易感肝癌的促癌和致癌 依赖于M6P/IGFII受体。这些研究的结果 应能更好地理解M6P/IGFII的作用 受体和转化生长因子β在促进肝癌中的作用，并使我们能够评估 对人类致癌风险的物质具有更高的准确性。

DESCRIPTION (adapted from the investigator's abstract): Hepatocellular carcinomas (HCC) are among the most common malignancies in the world with tumor incidence approaching 150 per 100,000 per year in areas such as China. Although the incidence of liver cancer is lower in the United States, 60 percent of the chemicals determined by the National Toxicology Program to be carcinogens give rise to liver tumors in rats and mice. Interestingly, a number of these agents appear to function through tumor promoting rather than initiating mechanisms. Consequently, to appropriately assess the high risk from xenobiotic agents, it is necessary to determine the molecular events by which liver tumor promoters enhance the formation of Hepatocellular carcinomas. The investigators have evidence that suggests liver tumor promotion by phenobarbital (PB) is a process of natural selection for cells resistant to the growth inhibitory environment produced by PB. The results also suggest that the selective increase in mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor and TGFbeta levels in normal hepatocytes is important in establishing the mito-inhibitory selective pressure required for PB to promote the formation of liver tumors. Both the activation of the growth inhibitor, TGFbeta, and the degradation of the mitogen, IGFII, depend upon their binding to the M6P/IGFII receptor. The M6P/IGFII receptor is imprinted in mice and potentially in a subset of humans. They have also recently found a 78 percent loss of heterozygosity (LOH) at the M6P/IGFII receptor gene locus in human HCCs. These findings strongly support the postulate that this receptor function as a tumor suppressor in liver carcinogenesis. Therefore, the overall objective of this grant application is to determine the role of the M6P/IGFII receptor and TGFbeta in liver carcinogenesis. Specifically, they have proposed to: 1) determine the transcriptional control elements responsible for the modulation of M6P/IGFII receptor gene expression; 2) determine whether reduced expression of the M6P/IGFII receptor in liver tumors results from altered gene methylation; 3) determine whether the extent of LOH at the M6P/IGFII receptor gene locus in human HCC is dependent upon the etiology and stage of tumor development; 4) identify mutations in the remaining allele in HCCs and LOH at the M6P/IGFII receptor locus; and 5) determine, using transgenic mice, whether susceptibility to liver tumor promotion and carcinogenesis is dependent upon the M6P/IGFII receptor. The results of these studies should provide a better understanding of the role of the M6P/IGFII receptor and TGFbeta in liver tumor promotion, and enable us to assess substances for human carcinogenic risk with greater accuracy.