Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis
Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis
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DOI：
10.1038/sj.onc.1204544
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发表时间：
2001-08-16
期刊：
影响因子：
8
通讯作者：
Blessing, M
中科院分区：
文献类型：
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作者：
Kanzler, S;Meyer, E;Blessing, M
转化生长因子-β（TGF-β）超家族细胞因子的强效生长抑制活性及其在上皮中的广泛表达表明它们可能在维持上皮内稳态方面发挥重要作用。为了分析肝中TGF-β介导的肿瘤抑制活性，我们在人C-反应蛋白基因启动子的调控元件的控制下产生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型和肝脏特异性转基因表达。在原代肝细胞培养物中，TGF-β诱导的DNA合成抑制减少，表明转基因肝细胞中TGF-β信号传导途径的功能失活。在转基因小鼠中，肝脏形态和自发性肿瘤发生没有变化，这表明在生理条件下，肝细胞中TGF-β的所有三种亚型的信号传导的中断不会干扰肝脏中的组织稳态。然而，以下启动与致癌物质二乙基亚硝胺和肿瘤促进苯巴比妥转基因小鼠表现出中度，但显着增加的发病率，大小和多样性的癌前组织病变的肝脏和肝细胞癌。这些结果提供了体内证据，表明在化学性肝癌发生过程中，肝脏中内源性TGF-β系统具有肿瘤抑制活性。
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 epithetial 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 endogeneous TGF-beta system in the liver during chemical hepatocarcinogenesis.