TUMOR SUPPRESSOR GENES IN HUMAN HEPATOCELLULAR CARCINOMA

使用单链构象多态性和测序的研究 用于鉴定几个人群中的p53突变。 突变 在11/35例（31%）肝细胞癌（HCC）中检测到p53基因 来自韩国。 这些突变中只有一个发生在密码子的"热点"位置 249，一种长期以来与黄曲霉毒素相关的突变， 可能的致病因素;因此，黄曲霉毒素似乎发挥很少 在韩国HCC的发展中发挥作用。 这符合 在韩国食品中缺乏黄曲霉毒素和突出的作用， 在韩国，B型肝炎病毒（HBV）是HCC病因。 在美国的一个实验室进行的类似研究 人口不寻常，因为： 1)虽然已经发现肿瘤抑制基因p53的突变 在许多国家的肝细胞癌（HCC）中， 常见的p53突变通过直接测序在HCC中检测到， 美国（HCC不常见）以前没有报告。 2)大多数研究集中在p53外显子4 - 9;所有p53外显子（1到9）都是p53外显子。 11)在这里首次被研究。 p53基因缺失 5/12例（42%）HCC中发现有HCCs。 在hot- 点密码子249;数据表明，黄曲霉毒素以外的因素可能 负责p53异常的患者来自美国。 使用野生型人源性重组腺病毒构建了重组痘苗病毒。 p53基因作为插入物。 该重组体产生的p53蛋白 病毒用于研究17个细胞系中的p53结合蛋白， 包括10个来自HCC，4个来自其他人类癌症， 从非人类灵长类动物的组织中提取 在测试的所有17个细胞系中;两个 鉴定出与野生型p53结合的40 kD和50 kD蛋白 并且其可能是p53功能的细胞调节剂。

Studies using single-strand conformation polymorphism and sequencing have been used to identify p53 mutations in several populations. Mutations of p53 were identified in 11/35 (31%) hepatocellular carcinomas (HCCs) from Korea. Only one of these mutations was at the "hot spot" at codon 249, a mutation that has long been associated with aflatoxin as a possible etiologic factor; thus, aflatoxin appears to play very little role in the development of HCC in Korea. This is consistent with the lack of aflatoxin in the food in Korea and the prominent role of hepatitis B virus (HBV) as a cause of HCC in Korea. Similar studies conducted in this laboratory in a United States population were unusual because: 1) Although mutations of the tumor suppressor gene p53 have been found in hepatocellular carcinomas (HCCs) from many countries where HCC is common, p53 mutations detected by direct sequencing in HCCs from the United States (where HCC is uncommon) have not been previously reported. 2) Most studies have focused on p53 exons 4-9; all p53 exons (1 through 11) were studied here for the first time. Abnormalities of the p53 gene were found in 5/12 (42%) HCCs. No mutations of p53 were found at hot- spot codon 249; the data suggest that factors other than aflatoxin may be responsible for the p53 abnormalities in the patients from the USA. A recombinant vaccinia virus was constructed using the wild-type human p53 gene as an insert. The p53 protein produced by this recombinant virus was used to investigate p53 binding proteins in 17 cell lines, including 10 derived from HCC, four from other human cancers, and three from non-human primate tissues. In all 17 cell lines tested; two proteins of 40 kD and 50 kD were identified that bound to wild-type p53 and that may be cellular regulators of p53 function.