TY - JOUR
T1 - Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis
T2 - Importance of TGF-β signalling in the control of liver homeostasis and transformation
AU - Amicone, Laura
AU - Terradillos, Olivier
AU - Calvo, Ludovica
AU - Costabile, Barbara
AU - Cicchini, Carla
AU - Della Rocca, Carlo
AU - Lozupone, Francesco
AU - Piacentini, Mauro
AU - Buendia, Marie Annick
AU - Tripodi, Marco
PY - 2002/2/21
Y1 - 2002/2/21
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Hepatocyte proliferation
KW - Liver mass homeostasis
KW - Oncogene cooperation
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U2 - 10.1038/sj/onc/1205199
DO - 10.1038/sj/onc/1205199
M3 - Article
C2 - 11857077
VL - 21
SP - 1335
EP - 1345
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 9
ER -