Background & Aims: Activating mutations of PIK3CA occur in various tumour types, including human hepatocellular carcinoma. The mechanisms whereby PIK3CA contributes to hepatocarcinogenesis remain poorly understood. Methods: PIK3CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NRasV12 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 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. Conclusions: 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.

Activated mutant forms of PIK3CA cooperate with RasV12 or c-Met to induce liver tumour formation in mice via AKT2/mTORC1 cascade / Wang, Chunmei; Che, Li; Hu, Junjie; Zhang, Shanshan; Jiang, Lijie; Latte, Gavinella; Demartis, Maria Ilaria; Tao, Junyan; Gui, Bing; Pilo, Maria Giulia; Ribback, Silvia; Dombrowski, Frank; Evert, Matthias; Calvisi, Diego Francesco; Chen, Xin. - In: LIVER INTERNATIONAL. - ISSN 1478-3223. - 36:8(2016), pp. 1176-1186. [10.1111/liv.13055]

Activated mutant forms of PIK3CA cooperate with RasV12 or c-Met to induce liver tumour formation in mice via AKT2/mTORC1 cascade

LATTE, Gavinella;DEMARTIS, Maria Ilaria;PILO, Maria Giulia;CALVISI, Diego Francesco;
2016-01-01

Abstract

Background & Aims: Activating mutations of PIK3CA occur in various tumour types, including human hepatocellular carcinoma. The mechanisms whereby PIK3CA contributes to hepatocarcinogenesis remain poorly understood. Methods: PIK3CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NRasV12 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 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. Conclusions: 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.
2016
Activated mutant forms of PIK3CA cooperate with RasV12 or c-Met to induce liver tumour formation in mice via AKT2/mTORC1 cascade / Wang, Chunmei; Che, Li; Hu, Junjie; Zhang, Shanshan; Jiang, Lijie; Latte, Gavinella; Demartis, Maria Ilaria; Tao, Junyan; Gui, Bing; Pilo, Maria Giulia; Ribback, Silvia; Dombrowski, Frank; Evert, Matthias; Calvisi, Diego Francesco; Chen, Xin. - In: LIVER INTERNATIONAL. - ISSN 1478-3223. - 36:8(2016), pp. 1176-1186. [10.1111/liv.13055]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/178227
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