title: Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway.
abstract: OBJECTIVE
  Some clinical findings have suggested that systemic metabolic disorders accelerate in vivo tumor progression. Deregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is implicated in both metabolic dysfunction and carcinogenesis in humans; however, it remains unknown whether the altered metabolic status caused by abnormal activation of the pathway is linked to the protumorigenic effect.
  
  
  METHODS
  We established hepatocyte-specific Pik3ca transgenic (Tg) mice harboring N1068fs*4 mutation.
  
  
  RESULTS
  The Tg mice exhibited hepatic steatosis and tumor development. PPARγ-dependent lipogenesis was accelerated in the Tg liver, and the abnormal profile of accumulated fatty acid (FA) composition was observed in the tumors of Tg livers. In addition, the Akt/mTOR pathway was highly activated in the tumors, and in turn, the expression of tumor suppressor genes including Pten, Xpo4, and Dlc1 decreased. Interestingly, we found that the suppression of those genes and the enhanced in vitro colony formation were induced in the immortalized hepatocytes by the treatment with oleic acid (OA), which is one of the FAs that accumulated in tumors.
  
  
  CONCLUSIONS
  Our data suggest that the unusual FA accumulation has a possible role in promoting in vivo hepato-tumorigenesis under constitutive activation of the PI3K pathway. The Pik3ca Tg mice might help to elucidate molecular mechanisms by which metabolic dysfunction contributes to in vivo tumor progression.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Kudo
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tateishi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Shinzo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Dai
authors.initials: D
authors.lastname: Mohri
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Isomura
authors.forename: Motoko
authors.initials: M
authors.lastname: Seto
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Motohisa
authors.initials: M
authors.lastname: Tada
authors.forename: Miki
authors.initials: M
authors.lastname: Ohta
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Shiina
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakajima
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kanai
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000818:Animals; D001483:Base Sequence; D058534:Class I Phosphatidylinositol 3-Kinases; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D004789:Enzyme Activation; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D009829:Oleic Acids / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D017931:DNA Primers; D005227:Fatty Acids; D050505:Mutant Proteins; D009829:Oleic Acids; D010169:Palmitic Acids; D019869:Phosphatidylinositol 3-Kinases; D011994:Recombinant Proteins; C546639:Pik3ca protein, mouse