Kanzler S, Meyer E, Lohse A W, Schirmacher P, Henninger J, Galle P R, Blessing M
Department of Medicine, University of Mainz, 55131 Mainz, Germany.
Oncogene. 2001 Aug 16;20(36):5015-24. doi: 10.1038/sj.onc.1204544.
The potent growth-inhibitory activity of cytokines of the transforming growth factor-beta (TGF-beta) superfamily and their widespread expression in epithelia suggest that they may play an important role in the maintenance of epithelial homeostasis. To analyse TGF-beta mediated tumor suppressor activity in the liver, we generated transgenic mice overexpressing a dominant negative type II TGF-beta receptor in hepatocytes under control of the regulatory elements of the human C-reactive protein gene promoter. Transgenic animals exhibited constitutive and liver-specific transgene expression. The functional inactivation of the TGF-beta signaling pathway in transgenic hepatocytes was shown by reduced TGF-beta induced inhibition of DNA synthesis in primary hepatocyte cultures. Liver morphology and spontaneous tumorigenesis were unchanged in transgenic mice suggesting that interruption of the signaling of all three isoforms of TGF-beta in hepatocytes does not disturb tissue homeostasis in the liver under physiological conditions. However, following initiation with the carcinogen diethylnitrosamine and tumor-promotion with phenobarbital transgenic mice exhibited a moderate albeit significant increase in the incidence, size and multiplicity of both preneoplastic tissue lesions in the liver and of hepatocellular carcinomas. These results give in vivo evidence for a tumor suppressor activity of the endogenous TGF-beta system in the liver during chemical hepatocarcinogenesis.
转化生长因子-β（TGF-β）超家族细胞因子强大的生长抑制活性及其在上皮细胞中的广泛表达表明，它们可能在维持上皮细胞稳态中发挥重要作用。为了分析TGF-β在肝脏中介导的肿瘤抑制活性，我们利用人C反应蛋白基因启动子的调控元件，构建了在肝细胞中过表达显性负性II型TGF-β受体的转基因小鼠。转基因动物表现出组成性和肝脏特异性的转基因表达。在原代肝细胞培养中，转基因肝细胞中TGF-β诱导的DNA合成抑制作用降低，表明TGF-β信号通路功能失活。转基因小鼠的肝脏形态和自发肿瘤发生情况未发生改变，这表明在生理条件下，肝细胞中所有三种TGF-β同工型信号的中断不会干扰肝脏的组织稳态。然而，在用致癌物二乙基亚硝胺启动并以苯巴比妥进行肿瘤促进后，转基因小鼠肝脏中的癌前组织病变和肝细胞癌的发生率、大小和数量均出现了适度但显著的增加。这些结果为内源性TGF-β系统在化学性肝癌发生过程中对肝脏的肿瘤抑制活性提供了体内证据。
