title: Activated mutant forms of PIK3CA cooperate with RasV12 or c-Met to induce liver tumour formation in mice via AKT2/mTORC1 cascade.
abstract: Activating mutations of PIK3CA occur in various tumour types, including human hepatocellular carcinoma. The mechanisms whereby PIK3CA contributes to hepatocarcinogenesis remain poorly understood.
  
  
  
  PIK3CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NRasV12 or c-Met genes, in the mouse liver.
  
  
  
  Overexpression of H1047R or E545K alone was able to induce AKT/mTOR signalling in the mouse liver, leading to hepatic steatosis. However, none of the mice developed liver tumours over long term. In contrast, H1047R or E545K cooperated with NRasV12 or c-Met to rapidly induce liver tumour formation in mice. At the molecular level, all the tumour nodules displayed activation of AKT/mTOR and Ras/MAPK cascades. Ablation of AKT2 significantly inhibited hepatic steatosis induced by H1047R or E545K and carcinogenesis induced by H1047R/c-Met or E545K/c-Met. Furthermore, tumourigenesis induced by H1047R/c-Met was abolished in conditional Raptor knockout mice.
  
  
  
  Both H1047R and E545K are able to activate the AKT/mTOR pathway. An intact AKT2/mTOR complex 1 cascade is required for tumourigenesis induced by H1047R/c-Met or E545K/c-Met in the liver.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|Division of Oncology, Key Laboratory of Carcinogenesis and Translational Research of the Ministry of Education, Peking University Cancer Hospital and Institute, Beijing, P. R. China.
authors.forename: Li
authors.identifier: 0000-0001-7971-8725
authors.initials: L
authors.lastname: Che
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P. R. China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, P. R. China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Lijie
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Gavinella
authors.initials: G
authors.lastname: Latte
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Demartis
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P. R. China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Gui
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pilo
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D058534:Class I Phosphatidylinositol 3-Kinases; D005234:Fatty Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C546843:mTOR protein, mouse; C546639:Pik3ca protein, mouse; C494922:Akt2 protein, mouse
keywords: AKT/mTOR; NRasV12; PIK3CA mutants; c-Met; liver cancer