Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: Importance of TGF-β signalling in the control of liver homeostasis and transformation

Laura Amicone, Olivier Terradillos, Ludovica Calvo, Barbara Costabile, Carla Cicchini, Carlo Della Rocca, Francesco Lozupone, Mauro Piacentini, Marie Annick Buendia, Marco Tripodi

Research output: Contribution to journalArticlepeer-review

Abstract

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-β1 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-β receptor type II expression was strongly downregulated in most tumours, indicating that impairment of TGF-β1-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.

Original languageEnglish
Pages (from-to)1335-1345
Number of pages11
JournalOncogene
Volume21
Issue number9
DOIs
Publication statusPublished - Feb 21 2002

Keywords

  • Apoptosis
  • Hepatocyte proliferation
  • Liver mass homeostasis
  • Oncogene cooperation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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