Exp Mol Med.
2018 Jan;50(1):e417. 10.1038/emm.2017.158.
Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway
- Affiliations
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- 1Department of Gastroenterology, Guizhou Provincial People's Hospital, The Affiliated People's Hospital of Guizhou Medical University, Guiyang, PR China.
- 2Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA. xin.chen@ucsf.edu
- 3School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, PR China.
- 4Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, PR China.
- 5Institute of Pathology, University of Greifswald, Greifswald, Germany. diego.calvisi@uni-greifswald.de
- 6Lowell High School, San Francisco, CA, USA.
- 7Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.
- KMID: 2438347
- DOI: http://doi.org/10.1038/emm.2017.158
Abstract
- Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Activation of the AKT/mTOR cascade is one of the most frequent events along hepatocarcinogenesis. mTOR is a serine/threonine kinase and presents in two distinct complexes: mTORC1 and mTORC2. While mTORC1 has been extensively studied in HCC, the functional contribution of mTORC2 during hepatocarcinogenesis has not been well characterized, especially in vivo. Pten expression is one of the major mechanisms leading to the aberrant activation of the AKT/mTOR signaling. Here, we show that concomitant downregulation of Pten and upregulation of c-Met occurs in a subset of human HCC, mainly characterized by poor prognosis. Using CRISPR-based gene editing in combination with hydrodynamic injection, Pten was deleted in a subset of mouse hepatocytes (sgPten). We found that loss of Pten synergizes with overexpression of c-Met to promote HCC development in mice (sgPten/c-Met). At the molecular level, sgPten/c-Met liver tumor tissues display increased AKT and mTOR signaling. Using Rictor conditional knockout mice, we demonstrate that sgPten/c-Met-driven HCC development strictly depends on an intact mTORC2 complex. Our findings therefore support the critical role of mTORC2 in hepatocarcinogenesis. sgPten/c-Met mouse model represents a novel valuable system that can be used for the development of targeted therapy against this deadly malignancy.
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