title: Bak deficiency inhibits liver carcinogenesis: a causal link between apoptosis and carcinogenesis.
abstract: OBJECTIVE
  Hepatocyte apoptosis is a key feature of chronic liver disease including viral hepatitis and steatohepatitis. A previous study demonstrated that absence of the Bcl-2 family protein Mcl-1 led to increased hepatocyte apoptosis and development of liver tumors in mice. Since Mcl-1 not only inhibits the mitochondrial pathway of apoptosis but can also inhibit cell cycle progression and promote DNA repair, it remains to be proven whether the tumor suppressive effects of Mcl-1 are mediated by prevention of apoptosis.
  
  
  METHODS
  We examined liver tumor development, fibrogenesis, and oxidative stress in livers of hepatocyte-specific knockout (KO) of Mcl-1 or Bcl-xL, another key antagonist of apoptosis in hepatocytes. We also examined the impact of additional KO of Bak, a downstream molecule of Mcl-1 towards apoptosis but not the cell cycle or DNA damage pathway, on tumor development, hepatocyte apoptosis, and inflammation.
  
  
  RESULTS
  Bcl-xL KO led to a high incidence of liver tumors in 1.5-year-old mice, similar to Mcl-1 KO. Bcl-xL- or Mcl-1-deficient livers showed higher levels of TNF-α production and oxidative stress than wild-type livers at as early as 6 weeks of age and oxidative DNA damage at 1.5 years. Deletion of Bak significantly inhibited hepatocyte apoptosis in Mcl-1 KO mice and reduced the incidence of liver cancer, coinciding with reduction of TNF-α production, oxidative stress, and oxidative DNA damage in non-cancerous livers.
  
  
  CONCLUSIONS
  Our findings strongly suggest that chronically increased apoptosis in hepatocytes is carcinogenic and offer genetic evidence that inhibition of apoptosis may suppress liver carcinogenesis in chronic liver disease.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Minoru
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005838:Genotype; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018384:Oxidative Stress / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine