Dual functions of E2F-1 in a transgenic mouse model of liver carcinogenesis
Dual functions of E2F-1 in a transgenic mouse model of liver carcinogenesis
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DOI：
10.1038/sj.onc.1203885
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发表时间：
2000-10-19
期刊：
影响因子：
8
通讯作者：
Thorgeirsson, SS
中科院分区：
文献类型：
--
作者：
Conner, EA;Lemmer, ER;Thorgeirsson, SS
E2 F转录控制的失调与致癌转化有关。与这一想法一致，我们最近证明，在c-myc/TGF α双转基因小鼠的肝癌发生过程中，E2 F-1和E2 F-2的表达增加，以及推定的E2 F靶基因的诱导。因此，我们产生了在白蛋白增强子/启动子控制下表达E2 F-1的转基因小鼠，以测试E2 F家族成员可能有助于肝肿瘤发展的假设。E2 F-1的过度表达导致出生后肝脏生长过程中细胞增殖和死亡的轻度但持续的增加，并且部分肝切除术后肝脏再生生长没有增加。然而，从出生后2个月E2 F-1转基因小鼠表现出突出的肝脏组织学异常，包括癌前病灶附近的汇管区和中央周围的大细胞发育不良。从6到8个月开始，肿瘤结节（“腺瘤”）的数量突然增加，到10个月时发病率为100%。一些腺瘤搁置恶性转化的证据，在IZ个月杀死的六只小鼠中有两只显示小梁状肝细胞癌。内源性c-myc在E2 F-1肝癌发生的早期阶段上调，而p53在肿瘤中过表达，表明E2 F-1介导的增殖和凋亡都是可操作的，但在肝癌发生的不同阶段。总之，E2 F-1在肝脏中的过度表达导致发育不良和肿瘤，并建议在肝脏肿瘤发生过程中E2 F-1和c-myc癌基因之间的合作。
Deregulation of E2F transcriptional control has been implicated in oncogenic transformation. Consistent with this idea, we recently demonstrated that during hepatocarcinogenesis in c-myc/TGF alpha double transgenic mice, there is increased expression of E2F-1 and E2F-2, as well as induction of putative E2F target genes. Therefore, we generated transgenic mice expressing E2F-1 under the control of the albumin enhancer/promoter to test the hypothesis that E2F family members may contribute to liver tumor development. Overexpression of E2F-1 resulted in mild but persistent increases in cell proliferation and death during postnatal liver growth, and no increases in hepatic regenerative growth in response to partial hepatectomy. Nevertheless, from 2 months postnatally E2F-1 transgenic mice exhibited prominent hepatic histological abnormalities including preneoplastic foci adjacent to portal tracts and pericentral large cell dysplasia. From 6 to 8 months onward, there was an abrupt increase in the number of neoplastic nodules ('adenomas') with 100% incidence by 10 months. Some adenomas shelved evidence of malignant transformation, and two of six mice killed at IZ months showed trabecular hepatocellular carcinoma. Endogenous c-myc was up-regulated in the early stages of E2F-1 hepatocarcinogenesis, whereas p53 was overexpressed in the tumors, suggesting that both E2F-1-mediated proliferation and apoptosis are operative but at different stages of hepatocarcinogenesis. In conclusion, E2F-1 overexpression in the liver causes dysplasia and tumors and suggests a cooperation between E2F-1 and c-myc oncogenes during liver oncogenesis.