Wang, Chunmei and Che, Li and Hu, Junjie and Zhang, Shanshan and Jiang, Lijie and Latte, Gavinella and Demartis, Maria I. and Tao, Junyan and Gui, Bing and Pilo, Maria G. and Ribback, Silvia and Dombrowski, Frank and Evert, Matthias and Calvisi, Diego F. and Chen, Xin (2016) Activated mutant forms of PIK3CA cooperate with RasV12 or c-Met to induce liver tumour formation in mice via AKT2/mTORC1 cascade. LIVER INTERNATIONAL, 36 (8). pp. 1176-1186. ISSN 1478-3223, 1478-3231
Full text not available from this repository. (Request a copy)Abstract
Background & AimsActivating mutations of PIK3CA occur in various tumour types, including human hepatocellular carcinoma. The mechanisms whereby PIK3CA contributes to hepatocarcinogenesis remain poorly understood. MethodsPIK3CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NRasV12 or c-Met genes, in the mouse liver. ResultsOverexpression 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. ConclusionsBoth 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATOCELLULAR-CARCINOMA; HUMAN CANCER; COMPLEX 1; PTEN-LOSS; PATHWAY; TARGET; MOUSE; AKT2; HEPATOCARCINOGENESIS; OPPORTUNITIES; AKT/mTOR; c-Met; liver cancer; NRasV12; PIK3CA mutants |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Mar 2019 10:16 |
| Last Modified: | 22 Mar 2019 10:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3596 |
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