title: Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans.
abstract: OBJECTIVE
  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.
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Giulia M
authors.initials: GM
authors.lastname: Pilo
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA; Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Li
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Gavinella
authors.initials: G
authors.lastname: Latte
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Che
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Christy
authors.initials: C
authors.lastname: Joseph
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Mela
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Lijie
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Simile
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pascale
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy. Electronic address: calvisid@uniss.it.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Fatty acid synthase; Hepatocellular carcinoma; Lipogenesis; Rictor