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

Liver Int. 2016 Aug;36(8):1176-86. doi: 10.1111/liv.13055. Epub 2016 Jan 30.

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.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / pathology
  • Cell Transformation, Neoplastic
  • Class I Phosphatidylinositol 3-Kinases
  • Fatty Liver / pathology
  • Liver Neoplasms / pathology*
  • Mice
  • Mice, Knockout
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / genetics
  • ras Proteins / metabolism*

Substances

  • mTOR protein, mouse
  • Class I Phosphatidylinositol 3-Kinases
  • Pik3ca protein, mouse
  • Proto-Oncogene Proteins c-met
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • ras Proteins