title: Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice.
abstract: 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.
authors: School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors: Junjie
authors: J
authors: Hu
authors: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, P. R. China.
authors: Li
authors: L
authors: Che
authors: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
authors: Lei
authors: L
authors: Li
authors: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors: Maria G
authors: MG
authors: Pilo
authors: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors: Antonio
authors: A
authors: Cigliano
authors: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors: Silvia
authors: S
authors: Ribback
authors: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
authors: Xiaolei
authors: X
authors: Li
authors: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors: Gavinella
authors: G
authors: Latte
authors: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors: Marta
authors: M
authors: Mela
authors: Institute of Pathology, University of Regensburg, Regensburg, Germany.
authors: Matthias
authors: M
authors: Evert
authors: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors: Frank
authors: F
authors: Dombrowski
authors: School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.
authors: Guohua
authors: G
authors: Zheng
authors: School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors: Xin
authors: X
authors: Chen
authors: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors: Diego F
authors: DF
authors: Calvisi
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D054890:Fatty Acid Synthase, Type I; D019859:Proto-Oncogene Proteins c-met; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases