Hu, Junjie and Che, Li and Li, Lei and Pilo, Maria G. and Cigliano, Antonio and Ribback, Silvia and Li, Xiaolei and Latte, Gavinella and Mela, Marta and Evert, Matthias and Dombrowski, Frank and Zheng, Guohua and Chen, Xin and Calvisi, Diego F. (2016) Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice. SCIENTIFIC REPORTS, 6: 20484. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)Abstract
Activation of the AKT/mTOR cascade and overexpression of c-Met have been implicated in the development of human hepatocellular carcinoma (HCC). To elucidate the functional crosstalk between the two pathways, we generated a model characterized by the combined expression of activated AKT and c-Met in the mouse liver. Co-expression of AKT and c-Met triggered rapid liver tumor development and mice required to be euthanized within 8 weeks after hydrodynamic injection. At the molecular level, liver tumors induced by AKT/c-Met display activation of AKT/mTOR and Ras/MAPK cascades as well as increased lipogenesis and glycolysis. Since a remarkable lipogenic phenotype characterizes liver lesions from AKT/c-Met mice, we determined the requirement of lipogenesis in AKT/c-Met driven hepatocarcinogenesis using conditional Fatty Acid Synthase (FASN) knockout mice. Of note, hepatocarcinogenesis induced by AKT/c-Met was fully inhibited by FASN ablation. In human HCC samples, coordinated expression of FASN, activated AKT, and c-Met proteins was detected in a subgroup of biologically aggressive tumors. Altogether, our study demonstrates that co-activation of AKT and c-Met induces HCC development that depends on the mTORC1/FASN pathway. Suppression of mTORC1 and/or FASN might be highly detrimental for the growth of human HCC subsets characterized by concomitant induction of the AKT and c-Met cascades.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FATTY-ACID SYNTHASE; THERAPEUTIC TARGET; N-RAS; LIVER; CANCER; EXPRESSION; RECEPTOR; GROWTH; MOUSE; INHIBITION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Mar 2019 12:09 |
| Last Modified: | 12 Mar 2019 12:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2409 |
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