Jia, Jiaoyuan and Che, Li and Cigliano, Antonio and Wang, Xue and Peitta, Graziella and Tao, Junyan and Zhong, Sheng and Ribback, Silvia and Evert, Matthias and Chen, Xin and Calvisi, Diego F. (2020) Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21 (22): 8467. ISSN , 1422-0067
Full text not available from this repository. (Request a copy)Abstract
Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; FASN; lipogenesis; hepatocellular carcinoma; c-Myc; mouse models |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2021 09:42 |
| Last Modified: | 08 Mar 2021 09:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43443 |
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