The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice
The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice
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DOI：
10.1002/hep.510270411
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发表时间：
1998-04-01
期刊：
影响因子：
13.5
通讯作者：
Sell, S
中科院分区：
文献类型：
--
作者：
Ghebranious, N;Sell, S
在转基因小鼠模型，即在截短的白蛋白启动子控制下表达突变蛋白基因的转基因p53 ser 246小鼠中，将在与黄曲霉毒素（AFB 1）暴露相关的人肝细胞癌中发现的相当于人p53 ser 249突变的小鼠对肝细胞癌发展的相对贡献与其他主要危险因素进行比较，与缺乏p53（p53 -/-）的小鼠和表达B型肝炎表面抗原（HBsAg）的转基因小鼠交配。然后通过测定13个月大时高级别肝肿瘤的数量，确定具有单一或多种风险因素的后代中的AFB 1肝癌发生。在AFB 1处理的雄性小鼠中，p53 ser 246突变的表达使高级别肿瘤的发生率在HBeAg阴性，p53 +/+（野生型纯合）对照小鼠中从0%增加到14%;在HBeAg阴性，p53 +/-（野生型杂合）小鼠中从14%增加到71%;在HBeAg阳性，p53 +/+小鼠中从62%增加到100%。因此，而HBsAg的表达和AFB 1一起是强烈的共致癌，p53 ser 246突变体的存在不仅显着增强这种共致癌作用，它也增加了AFB 1治疗的p53杂合子和纯合子小鼠不表达HBsAg的肿瘤发生，p53 ser 246突变蛋白可能作为AFB 1肝癌发生的促进剂的可能性进行了讨论。
The relative contribution to development of hepatocellular carcinoma of the mouse equivalent to the human p53ser249 mutation, found in human hepatocellular carcinoma associated with aflatoxin (AFB1) exposure, is compared with other major risk factors in a transgenic mouse model, Transgenic p53ser246 mice, expressing the mutant protein gene under the control of a truncated albumin promoter, were bred to mice lacking p53 (p53 -/-) and to transgenic mice expressing hepatitis B surface antigen (HBsAg). AFB1 hepatocarcinogenesis was then determined in offspring with single or multiple risk factors by determination of the numbers of high-grade hepatic tumors at 13 months of age. In AFB1-treated male mice, expression of the p53ser246 mutation increases the incidence of high-grade tumors from 0% to 14% in HBsAg-negative, p53 +/+ (wild-type homozygous) control mice; from 14% to 71% in HBsAg-negative, p53 +/- (wild-type heterozygous) mice; and from 62% to 100% in HBsAg-positive, p53 +/+ mice. Thus, whereas HBsAg expression and AFB1 together are strongly cocarcinogenic, the presence of the p53ser246 mutant not only significantly enhances this cocarcinogenic effect, it also increases tumorigenesis in AFB1-treated p53 heterozygous and homozygous mice not expressing HBsAg, The possibility that the p53ser246 mutant protein may act as a promoting agent for AFB1 hepatocarcinogenesis is discussed.