Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma: a prospective study

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• 作者：Atsushi Kudo (1)
  Kaoru Mogushi (2)
  Tadatoshi Takayama (3)
  Satoshi Matsumura (1)
  Daisuke Ban (1)
  Takumi Irie (1)
  Takanori Ochiai (1)
  Noriaki Nakamura (1)
  Hiroshi Tanaka (2)
  Naohiko Anzai (5)
  Michiie Sakamoto (4)
  Shinji Tanaka (1)
  Shigeki Arii (1)
  
• 关键词：Hepatocellular carcinoma ; Mitochondria ; Sirtuin 3 ; SLC22A7 ; Organic anion transporter
• 刊名：Journal of Gastroenterology
• 出版年：2014
• 出版时间：March 2014
• 年：2014
• 卷：49
• 期：3
• 页码：502-510
• 全文大小：5,327 KB
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• 作者单位：Atsushi Kudo (1)
  Kaoru Mogushi (2)
  Tadatoshi Takayama (3)
  Satoshi Matsumura (1)
  Daisuke Ban (1)
  Takumi Irie (1)
  Takanori Ochiai (1)
  Noriaki Nakamura (1)
  Hiroshi Tanaka (2)
  Naohiko Anzai (5)
  Michiie Sakamoto (4)
  Shinji Tanaka (1)
  Shigeki Arii (1)
  
  1. Department of Hepatobiliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
  2. Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
  3. Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
  5. Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, 321-0293, Japan
  4. Department of Pathology, Graduate School of Medicine, Keio University, Tokyo, Japan
  
• ISSN：1435-5922

文摘

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).