Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73
Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73
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DOI：
10.1093/carcin/bgm236
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发表时间：
2008-01-01
期刊：
影响因子：
4.7
通讯作者：
Puetzer, Brigitte M.
中科院分区：
文献类型：
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作者：
Tannapfel, Andrea;John, Katja;Puetzer, Brigitte M.
p53家族蛋白具有广泛的生物学功能，包括分化、细胞周期阻滞、凋亡和肿瘤的化疗敏感性。相反，N-末端截短的p73（DNp 73）作为所有这些肿瘤抑制特性的有效抑制剂发挥作用，暗示其参与恶性转化和肿瘤发生。一些报道表明肝细胞癌（HCC）中DNp 73的显著上调与患者存活率降低相关，但由于缺乏合适的模型，关于DNp 73在体内肿瘤发生中的功能意义知之甚少。为了解决这一问题，我们产生了转基因小鼠，其中DNp 73的表达是由白蛋白启动子引导到肝脏的。通过mRNA和蛋白质分析测试基因表达。转基因小鼠表现出明显的肝组织学异常，包括肝细胞增殖增加，导致3-4个月时的癌前病变（肝细胞腺瘤）。在12至20个月大的小鼠中，83%的动物患上了肝癌。HCC显示过度磷酸化的非活性视网膜母细胞瘤显著增加，而p53调节的细胞周期进展抑制剂在肿瘤中下调。我们的数据坚定地确立了DNp 73在体内驱动肝癌发生的独特致癌能力，支持其作为患者疾病严重程度的标志物和癌症预防靶点的重要性。该模型为进一步描述DNp 73介导的肝癌发生提供了新的机会，但也可能使更有效的癌症治疗方法的开发成为可能。
p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis and chemosensitivity of tumors. Conversely, N-terminally truncated p73 (DNp73) functions as a potent inhibitor of all these tumor suppressor properties, implicating its participation in malignant transformation and oncogenesis. Several reports indicated considerable up-regulation of DNp73 in hepatocellular carcinoma (HCC) that correlates with reduced survival of patients, but little is known about the functional significance of DNp73 to tumorigenesis in vivo due to the lack of an appropriate model. To address this, we generated transgenic mice in which DNp73 expression is directed to the liver by the albumin promoter. Gene expression was tested by mRNA and protein analyses. Transgenic mice exhibited prominent hepatic histological abnormalities including increased hepatocyte proliferation resulting in preneoplastic lesions (liver cell adenomas) at 3-4 months. Among 12- to 20-month-old mice, 83% of animals developed hepatic carcinoma. HCC displayed a significant increase of hyperphosphorylated inactive retinoblastoma, whereas p53-regulated inhibitors of cell cycle progression were down-regulated in the tumors. Our data firmly establish the unique oncogenic capability of DNp73 to drive hepatocarcinogenesis in vivo, supporting its significance as a marker for disease severity in patients and as target for cancer prevention. This model offers new opportunities to further delineate DNp73-mediated liver oncogenesis but may also enable the development of more effective cancer therapies.