title: Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma: a prospective study.
abstract: BACKGROUND
  Recurrence determines the postoperative prognosis with hepatocellular carcinoma (HCC). It is unknown how the liver dysfunction involving organic anion transporter failure causes the occurrence of HCCs. This study was designed to elucidate the link between liver dysfunction and multicentric occurrence (MO) after radical hepatectomy.
  
  
  METHODS
  Forty-nine samples of noncancerous liver tissue from HCC patients within the Milan criteria who were treated at our institution between January 2004 and August 2008 were examined as a training set by using genome-wide gene expression analysis. Using the independent 2-institutional cohort of 134 patients between September 2008 and December 2009, we performed a validation study using tissue microarray analysis. Cox proportional hazard regression analyses for MFS were performed to estimate the risk factors.
  
  
  RESULTS
  In the Gene Ontology database (GO:0015711), SLC22A7 expression was the best predictor of MO-free survival [MFS] (Fold, 0.726; P = 0.001). High SLC22A7 gene expression prevented the occurrence of HCC after hepatectomy (odds ratio [OR], 0.2; P = 0.004). Multivariate analyses identified SLC22A7 expression as an independent risk factor (OR, 0.3; P = 0.043). In the validation study, multivariate analyses of MFS identified SLC22A7 expression as an independent risk factor (OR, 0.5; P = 0.012). As judged by gene set enrichment analysis, SLC22A7 down regulation was associated with mitochondrion (P = 0.008) and oxidoreductase activity (P = 0.006). Sirtuin 3 as a regulator of mitochondrial metabolism also determined MFS (P = 0.018).
  
  
  CONCLUSIONS
  The mitochondrial pathways may affect SLC 22A7 function to promote the occurrence of HCC. (Word count: 246).
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan, kudomsrg@tmd.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kudo
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Takayama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ban
authors.forename: Takumi
authors.initials: T
authors.lastname: Irie
authors.forename: Takanori
authors.initials: T
authors.lastname: Ochiai
authors.forename: Noriaki
authors.initials: N
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arii
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000601:surgery; D005260:Female; D055106:Genome-Wide Association Study; D006498:Hepatectomy / Q000379:methods; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism*; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human
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