GROWTH FACTORS AND LIVER TUMOR PROMOTION

描述（改编自研究者摘要）：肝细胞 肝癌（HCC）是世界上最常见的恶性肿瘤之一， 肿瘤发病率接近150/100，000每年在地区， 中国 虽然肝癌的发病率在美国较低， 在美国，国家毒理学委员会确定的60%的化学物质 方案是致癌物引起大鼠和小鼠的肝脏肿瘤。 有趣的是，这些药物中的一些似乎通过肿瘤发挥作用。 促进而不是启动机制。 因而 适当评估外源性物质的高风险， 必须确定肝肿瘤的分子事件， 启动子增强肝细胞癌的形成。 的 研究人员有证据表明， 苯巴比妥（PB）是一个自然选择的过程， PB产生的生长抑制环境。 结果还 提示甘露糖6-磷酸/胰岛素样的选择性增加 生长因子II（M6 P/IGFII）受体和TGF β水平正常 肝细胞在建立有丝分裂抑制选择性 PB所需的压力，以促进肝肿瘤的形成。 两 生长抑制剂TGF β的活化和 有丝分裂原IGFII依赖于它们与M6 P/IGFII受体的结合。 M6 P/IGFII受体在小鼠中印迹，并且可能在一个子集中 人类 他们最近还发现， 人HCC中M6 P/IGDII受体基因座的杂合性（洛）。 这些发现有力地支持了这种受体 在肝癌发生过程中作为肿瘤抑制因子发挥作用。 因此 本补助金申请的总体目标是确定 M6 P/IGFII受体和TGF β在肝癌发生中作用 具体而言，他们提出：1）确定转录 负责调节M6 P/IGFII受体的控制元件 基因表达; 2）确定是否减少了基因表达， 肝肿瘤中M6 P/IGFII受体的基因甲基化改变 3)确定M6 P/IGFII受体基因的洛程度 人HCC中的基因座取决于肿瘤的病因和阶段 4）鉴定HCC中剩余等位基因的突变， M6 P/IGFII受体基因座的洛;和5）使用转基因技术， 小鼠是否易受肝癌的促进和致癌作用 依赖于M6 P/IGFII受体。 这些研究的结果 应更好地理解M6 P/IGFII的作用 受体和TGF β在肝肿瘤促进中的作用，使我们能够评估 更准确地评估人类致癌风险。

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.