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Activated mutant forms of PIK 3 CA cooperate with RasV12 or c‐Met to induce liver tumour formation in mice via AKT 2/ mTORC 1 cascade
Author(s) -
Wang Chunmei,
Che Li,
Hu Junjie,
Zhang Shanshan,
Jiang Lijie,
Latte Gavinella,
Demartis Maria I.,
Tao Junyan,
Gui Bing,
Pilo Maria G.,
Ribback Silvia,
Dombrowski Frank,
Evert Matthias,
Calvisi Diego F.,
Chen Xin
Publication year - 2016
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13055
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , steatosis , mutant , chemistry , microbiology and biotechnology , carcinogenesis , transfection , hepatocellular carcinoma , phosphorylation , cancer research , gene , endocrinology , signal transduction , biology , biochemistry
Background & Aims Activating mutations of PIK 3 CA occur in various tumour types, including human hepatocellular carcinoma. The mechanisms whereby PIK 3 CA contributes to hepatocarcinogenesis remain poorly understood. Methods PIK 3 CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NR asV12 or c‐Met genes, in the mouse liver. Results 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 NR asV12 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 AKT 2 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. Conclusions Both H1047R and E545K are able to activate the AKT / mTOR pathway. An intact AKT 2/ mTOR complex 1 cascade is required for tumourigenesis induced by H1047R/c‐Met or E545K/c‐Met in the liver.