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

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.

Keywords: AKT/mTOR; NRasV12; PIK3CA mutants; c-Met; liver cancer.