HUMAN LIVER CARCINOGENESIS

我们和其他人之前已经证明，249ser P53的频率 人肝细胞癌中的突变与 亚洲和亚洲癌症高危地区膳食黄曲霉毒素B1暴露 非洲。黄曲霉毒素B1暴露之间的剂量-反应关系 249serP53突变已扩展到北美，即， 墨西哥。此外，还检测到249ser p53突变细胞 非肿瘤性肝组织和这些突变细胞的频率是 与膳食黄曲霉毒素B1的估计剂量呈正相关 曝光。 我们以前曾报道过在A：T碱基上有高频率的P53突变 与氯乙烯暴露相关的肝血管肉瘤的配对。 这些数据与氯乙烯的环氧化物代谢物相一致。 与DNA中的脱氧腺苷结合。这些研究已经扩展到 检测非血管肉瘤的P53抑癌基因 与氯乙烯接触有关。P53基因突变谱系 不包括A：T碱基对的突变。此外，P53突变还包括 罕见的肝细胞癌与口服避孕药的使用有关。 乙型和丙型肝炎病毒也会导致人类肝癌的发生。 乙肝病毒X基因(HBX)在人类体内经常整合 来自高危地理区域的肝细胞癌。 因此，我们研究了HBx和P53蛋白的相互作用。 HBx与P53结合并抑制P53依赖的细胞凋亡，这可能 提高HBx表达细胞的存活率和克隆性 肝癌的发生。由于大约80%肝细胞癌产生甲胎蛋白 而启东、中国约50%的肝癌组织中存在249序列突变型P53，我们 发起了一项与癌症研究所的合作研究， 北京，将开发基因疗法(由甲胎蛋白驱动的p53 启动子)。

We and others have previously shown that the frequency of 249ser p53 mutation in human hepatocellular carcinoma is positively correlated with dietary aflatoxin B1 exposure in the high cancer risk areas of Asia and Africa. This dose-response relationship between aflatoxin B1 exposure and 249ser p53 mutations has been extended to North America, i.e., Mexico. In addition, 249ser p53 mutant cells have been detected in nontumorous liver tissue and the frequency of these mutant cells is positively correlated with estimated dose of dietary aflatoxin B1 exposure. We have previously reported a high frequency of p53 mutations at A:T base pairs in hepatic angiosarcoma associated with vinyl chloride exposure. These data are consistent with the epoxide metabolite of vinyl chloride binding to deoxyadenosine in DNA. These studies have been extended to examine the p53 tumor suppressor gene in angiosarcoma that is not associated with vinyl chloride exposure. The p53 mutational spectrum did not include mutations at A:T base pairs. In addition, p53 mutations were rare in hepatocellular carcinoma associated with oral contraceptive use. Hepatitis B and C viruses also contribute to human liver carcinogenesis. The hepatitis B viral X gene (HBx) is frequently integrated in human hepatocellular carcinomas (HCC) from high risk geographic regions. Therefore, we have investigated the interaction of HBx and p53 proteins. Hbx binds to p53 and inhibits p53-dependent apoptosis, which could increase the survival and clonal expansion of Hbx-expressing cells during liver carcinogenesis. Since about 80% of HCC produce alpha-fetoprotein and about 50% of HCC in Qidong, China contain a 249ser mutant p53, we have initiated a collaborative study with the Cancer Institute, C.A.M.S., Beijing, to develop gene therapy (p53 driven by alpha-fetoprotein promoter) of HCC.