Hepatitis B injury male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice
Hepatitis B injury male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice
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DOI：
10.1002/hep.510270211
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发表时间：
1998-02-01
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
在实验性转基因小鼠模型中，评估和比较了人类肝癌的主要危险因素：乙肝病毒(HBV)相关性肝损伤、男性、黄曲霉毒素暴露和P53表达。将在肝脏中表达乙肝表面抗原(HBs Ag)并在18月龄时发生肝肿瘤的转基因小鼠(HBV+鼠)与P53基因缺失的小鼠(p43-/-)杂交，产生P53+/-、HBV3+小鼠。这些小鼠和对照仔鼠([P53+/+，乙肝病毒+]，[P53+/-，乙肝病毒-]和[P53+/+，乙肝病毒-])在1周龄时被分成接受或不接受黄曲霉毒素注射的组。在13月龄处死时，100%(7/7)的雄性小鼠具有三种危险因素(P53+/-、HBV+、AFB(1)+)，发展为高级别肝细胞癌(HCC)。如果没有任何一个危险因素，发病率下降：如果两个P53等位基因都存在，发病率为62%(10/16)；如果没有表达HBs Ag，发病率为14%(1/7)；如果没有给予AFB(1)，发病率为25%(2/8)。如果只有一个危险因素存在，则没有发现I级以上的肿瘤。在雌性小鼠身上也观察到了类似的结果，只是每组小鼠的肝癌发病率都低于雄性小鼠。具有多种危险因素的小鼠中的一些肿瘤具有不寻常的组织类型，例如肝胆管癌、腺癌和未分化癌，这些在转乙肝病毒的C57BL/6小鼠中是不常见的。在任何肿瘤中都没有检测到p53基因的丢失或突变。在这些肝癌发生的转基因小鼠模型中，讨论了四个主要的肝癌危险因素如何相互作用以产生恶性肝肿瘤的可能性。
The major risk factors for human liver cancer: hepatitis B virus (HBV) related liver injury, male gender, aflatoxin exposure, and p53 expression, are evaluated and compared in experimental transgenic mouse models. Transgenic mice that express hepatitis B surface antigen (HBsAg) in their liver and develop liver tumors at 18 months of age (HBV+ mice) were bred to p53 null mice (p43-/-) to produce mice p53+/-, HBV+ mice. These mice and control littermates ([p53+/+, HBV+], [p53+/-, HBV-], and [p53+/+, HBV-]) were divided into groups that did or did not receive an injection of aflatoxin at 1 week of age. At sacrifice at 13 months of age, 100% (7/7) of male mice with each of the three risk factors (p53+/-, HBV+, AFB(1)+) developed high-grade hepatocellular carcinomas (HCC). If any one of the risk factors was absent, the incidence drops: if both p53 alleles are present, 62% (10/16); if HBsAg is not expressed, 14% (1/7); if AFB(1) is not given, 25% (2/8). If only one of the risk factors is present no tumors above grade I are found. Similar results were observed in female mice except that HCC incidence in each group is less than in male mice. Some of the tumors in mice with more than one risk factor are of unusual histological types, such as hepatocholangiocarcinomas, adenocarcinomas and undifferentiated carcinomas that are not usually seen in HBV transgenic C57BL/6 mice. No loss or mutation of the p53 gene is detected in any of the tumors. Possibilities of how the four major risk factors for HCC interact to produce malignant liver tumors in these transgenic mouse models of hepatocarcinogenesis are discussed.