Other
14 Authors
- Dombrowski F,
- Ribback S,
- Chen X,
- Li L,
- Calvisi DF,
- Li X,
- Hu J,
- Che L,
- Cigliano A,
- Zheng G,
- Latte G,
- Mela M,
- Evert M,
- Pilo MG
| First Author | Hu J | Year | 2016 |
| Journal | Sci Rep | Volume | 6 |
| Pages | 20484 | PubMed ID | 26857837 |
| Mgi Jnum | J:251102 | Mgi Id | MGI:6102406 |
| Doi | 10.1038/srep20484 | Citation | Hu J, et al. (2016) Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice. Sci Rep 6:20484 |
| abstractText | 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. |
