title: Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice co-expressing β-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis.
authors.affiliation: a Department of Bioengineering and Therapeutic Sciences , University of California , San Francisco , CA , USA.
authors.forename: Li
authors.initials: L
authors.lastname: Che
authors.affiliation: b Department of Clinical and Experimental Medicine , University of Sassari , Sassari , Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pilo
authors.affiliation: c Institute of Pathology, University Medicine Greifswald , Greifswald , Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.affiliation: b Department of Clinical and Experimental Medicine , University of Sassari , Sassari , Italy.
authors.forename: Gavinella
authors.initials: G
authors.lastname: Latte
authors.affiliation: b Department of Clinical and Experimental Medicine , University of Sassari , Sassari , Italy.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Simile
authors.affiliation: c Institute of Pathology, University Medicine Greifswald , Greifswald , Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: c Institute of Pathology, University Medicine Greifswald , Greifswald , Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: d Institute of Pathology, University of Regensburg , Regensburg , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.affiliation: a Department of Bioengineering and Therapeutic Sciences , University of California , San Francisco , CA , USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: b Department of Clinical and Experimental Medicine , University of Sassari , Sassari , Italy.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D064429:Fatty Acid Synthases / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009857:Oncogenes; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin; D064429:Fatty Acid Synthases; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D000103:Acetyl-CoA Carboxylase
keywords: AKT; FASN; c-Met; de novo lipogenesis; targeted therapies; β-catenin