Journal
JOURNAL OF HEPATOLOGY
Volume 64, Issue 2, Pages 333-341Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2015.10.004
Keywords
Hepatocellular carcinoma; Lipogenesis; Fatty acid synthase; AKT; Rictor
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Funding
- Italian Association Against Cancer (AIRC) [IG 12139]
- NIH [R01CA136606, R03CA165122]
- Deutsche Forschungsgemeinschaft DFG [Ev168/2-1]
- National Natural Science Foundation of China [81201553]
- UCSF Liver Center [P30DK026743]
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Background & Aims: Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver. Methods: FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA. Results: Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with a strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice. Conclusions: FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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