Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice

• Published in: Scientific reports Vol. 6; no. 1; p. 20484
• Main Authors: Hu, Junjie, Che, Li, Li, Lei, Pilo, Maria G., Cigliano, Antonio, Ribback, Silvia, Li, Xiaolei, Latte, Gavinella, Mela, Marta, Evert, Matthias, Dombrowski, Frank, Zheng, Guohua, Chen, Xin, Calvisi, Diego F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-02-2016; Nature Publishing Group
• Subjects: 13/51; 13/95; 38/77; 42/109; 631/67/395; 64/60; 692/4028/67/395; AKT protein; Animals; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Enzyme Activation; Fatty Acid Synthase, Type I - genetics; Fatty Acid Synthase, Type I - metabolism; Fatty-acid synthase; Glycolysis; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Lipogenesis; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; MAP kinase; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; multidisciplinary; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Rodents; Science; Signal Transduction; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep20484

Activation of the AKT/mTOR cascade and overexpression of c-Met have been implicated in the development of human hepatocellular carcinoma (HCC). To elucidate the functional crosstalk between the two pathways, we generated a model characterized by the combined expression of activated AKT and c-Met in the mouse liver. Co-expression of AKT and c-Met triggered rapid liver tumor development and mice required to be euthanized within 8 weeks after hydrodynamic injection. At the molecular level, liver tumors induced by AKT/c-Met display activation of AKT/mTOR and Ras/MAPK cascades as well as increased lipogenesis and glycolysis. Since a remarkable lipogenic phenotype characterizes liver lesions from AKT/c-Met mice, we determined the requirement of lipogenesis in AKT/c-Met driven hepatocarcinogenesis using conditional Fatty Acid Synthase (FASN) knockout mice. Of note, hepatocarcinogenesis induced by AKT/c-Met was fully inhibited by FASN ablation. In human HCC samples, coordinated expression of FASN, activated AKT and c-Met proteins was detected in a subgroup of biologically aggressive tumors. Altogether, our study demonstrates that co-activation of AKT and c-Met induces HCC development that depends on the mTORC1/FASN pathway. Suppression of mTORC1 and/or FASN might be highly detrimental for the growth of human HCC subsets characterized by concomitant induction of the AKT and c-Met cascades.