title: Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma.
abstract: OBJECTIVE
  De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC).
  
  
  METHODS
  We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo.
  
  
  RESULTS
  In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT-mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate-activated protein kinases. In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development.
  
  
  CONCLUSIONS
  De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.
authors.affiliation: Institut für Pathologie, Ernst-Moritz-Arndt-Universität, Greifswald, Germany. diego.calvisi@uni-greifswald.de
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Coral
authors.initials: C
authors.lastname: Ho
authors.forename: Sara
authors.initials: S
authors.lastname: Ladu
authors.forename: Susie A
authors.initials: SA
authors.lastname: Lee
authors.forename: Sandra
authors.initials: S
authors.lastname: Mattu
authors.forename: Giulia
authors.initials: G
authors.lastname: Destefanis
authors.forename: Salvatore
authors.initials: S
authors.lastname: Delogu
authors.forename: Antje
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Johan
authors.initials: J
authors.lastname: Ericsson
authors.forename: Stefania
authors.initials: S
authors.lastname: Brozzetti
authors.forename: Tommaso
authors.initials: T
authors.lastname: Staniscia
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D010450:Endopeptidases / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D050155:Lipogenesis; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D011506:Proteins / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014162:Transfection; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: C000715470:MAS1 protein, human; D046912:Multiprotein Complexes; D011506:Proteins; D000090063:Proto-Oncogene Mas; D038601:Ribosomal Protein S6; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D064429:Fatty Acid Synthases; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase