Amicone Laura, Terradillos Olivier, Calvo Ludovica, Costabile Barbara, Cicchini Carla, Della Rocca Carlo, Lozupone Francesco, Piacentini Mauro, Buendia Marie Annick, Tripodi Marco
Fondazione Istituto Pasteur-Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università La Sapienza, 00161, Rome, Italy.
Oncogene. 2002 Feb 21;21(9):1335-45. doi: 10.1038/sj.onc.1205199.
The c-Met tyrosine kinase receptor and its ligand, Hepatocyte Growth Factor/ Scatter Factor, have been implicated in human cancer. We have previously described that the transgenic expression of a truncated form of human c-Met (cyto-Met) in the liver confers resistance to several apoptotic stimuli. Here we show the impact of cyto-Met expression on liver proliferation and transformation. Despite a sixfold increase of hepatocyte proliferation, adult transgenic livers displayed normal size and architecture. We present evidence showing that activation of TGF-beta1 signalling controls the liver mass in cyto-Met mice. The oncogenic potential of cyto-Met was further assessed in the context of c-Myc-induced hepatocarcinogenesis, using WHV/c-Myc transgenic mice. Co-expression of cyto-Met and c-Myc further enhanced hepatocyte proliferation and caused a dramatic acceleration of the Myc-induced tumorigenesis, leading to the emergence of hepatocarcinomas in 3-4-month-old animals. Importantly, the TGF-beta receptor type II expression was strongly downregulated in most tumours, indicating that impairment of TGF-beta1-mediated growth inhibition plays a major role in accelerated neoplastic development. The strong potential of cyto-Met for oncogenic cooperation without direct transforming activity designates cyto-Met mice as an ideal tool for studying the early steps of multistage hepatocarcinogenesis and for identification of prognostic markers of transformation.
c-Met酪氨酸激酶受体及其配体肝细胞生长因子/分散因子与人类癌症有关。我们之前曾描述过，在肝脏中过表达截短形式的人类c-Met（细胞型c-Met，cyto-Met）可使肝脏对多种凋亡刺激产生抗性。在此，我们展示了cyto-Met表达对肝脏增殖和转化的影响。尽管肝细胞增殖增加了6倍，但成年转基因肝脏的大小和结构仍保持正常。我们提供的证据表明，TGF-β1信号通路的激活控制着cyto-Met小鼠的肝脏质量。我们利用土拨鼠肝炎病毒/c-Myc（WHV/c-Myc）转基因小鼠，在c-Myc诱导的肝癌发生背景下进一步评估了cyto-Met的致癌潜力。cyto-Met与c-Myc的共表达进一步增强了肝细胞增殖，并显著加速了Myc诱导的肿瘤发生，导致3至4月龄动物出现肝癌。重要的是，大多数肿瘤中II型TGF-β受体的表达强烈下调，这表明TGF-β1介导的生长抑制受损在加速肿瘤发展中起主要作用。cyto-Met具有很强的致癌协同作用潜力，但无直接转化活性，这使得cyto-Met小鼠成为研究多阶段肝癌发生早期步骤以及鉴定转化预后标志物的理想工具。
