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
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
Division of Oncology, Key Laboratory of Carcinogenesis and Translational Research of the Ministry of Education, Peking University Cancer Hospital and Institute, Beijing, P. R. China.
Liver Int. 2016 Aug;36(8):1176-86. doi: 10.1111/liv.13055. Epub 2016 Jan 30.
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.
PIK3CA mutants H1047R or E545K were hydrodynamically transfected, either alone or in combination with NRasV12 or c-Met genes, in the mouse liver.
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.
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.
PIK3CA的激活突变发生于多种肿瘤类型中，包括人类肝细胞癌。PIK3CA促进肝癌发生的机制仍知之甚少。
将PIK3CA突变体H1047R或E545K单独或与NRASV12或c-Met基因联合，通过流体动力学方法转染至小鼠肝脏。
单独过表达H1047R或E545K能够在小鼠肝脏中诱导AKT/mTOR信号传导，导致肝脂肪变性。然而，长期来看，没有小鼠发生肝肿瘤。相反，H1047R或E545K与NRASV12或c-Met协同作用，可快速诱导小鼠形成肝肿瘤。在分子水平上，所有肿瘤结节均显示出AKT/mTOR和Ras/MAPK级联的激活。敲除AKT2可显著抑制由H1047R或E545K诱导的肝脂肪变性以及由H1047R/c-Met或E545K/c-Met诱导的肿瘤发生。此外，在条件性Raptor基因敲除小鼠中，H1047R/c-Met诱导的肿瘤发生被消除。
H1047R和E545K均能够激活AKT/mTOR途径。肝脏中由H1047R/c-Met或E545K/c-Met诱导的肿瘤发生需要完整的AKT2/mTOR复合物1级联反应。
