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

Atsushi Kudo, Kaoru Mogushi, Tadatoshi Takayama, Satoshi Matsumura, Daisuke Ban, Takumi Irie, Takanori Ochiai, Noriaki Nakamura, Hiroshi Tanaka, Naohiko Anzai, Michiie Sakamoto, Shinji Tanaka, Shigeki Arii

Research output: Contribution to journalArticle

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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).

Original languageEnglish
Pages (from-to)502-510
Number of pages9
JournalJournal of Gastroenterology
Volume49
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

Hepatocellular Carcinoma
Prospective Studies
Survival
Validation Studies
Liver
Odds Ratio
Hepatectomy
Sirtuin 3
Liver Diseases
Multivariate Analysis
Tissue Array Analysis
Organic Anion Transporters
Gene Expression
Gene Ontology
Mitochondria
Oxidoreductases
Down-Regulation
Regression Analysis
Genome
Databases

Keywords

  • Hepatocellular carcinoma
  • Mitochondria
  • Organic anion transporter
  • Sirtuin 3
  • SLC22A7

ASJC Scopus subject areas

  • Gastroenterology
  • Medicine(all)

Cite this

Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma : A prospective study. / Kudo, Atsushi; Mogushi, Kaoru; Takayama, Tadatoshi; Matsumura, Satoshi; Ban, Daisuke; Irie, Takumi; Ochiai, Takanori; Nakamura, Noriaki; Tanaka, Hiroshi; Anzai, Naohiko; Sakamoto, Michiie; Tanaka, Shinji; Arii, Shigeki.

In: Journal of Gastroenterology, Vol. 49, No. 3, 2014, p. 502-510.

Research output: Contribution to journalArticle

Kudo, A, Mogushi, K, Takayama, T, Matsumura, S, Ban, D, Irie, T, Ochiai, T, Nakamura, N, Tanaka, H, Anzai, N, Sakamoto, M, Tanaka, S & Arii, S 2014, 'Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma: A prospective study', Journal of Gastroenterology, vol. 49, no. 3, pp. 502-510. https://doi.org/10.1007/s00535-013-0791-4
Kudo, Atsushi ; Mogushi, Kaoru ; Takayama, Tadatoshi ; Matsumura, Satoshi ; Ban, Daisuke ; Irie, Takumi ; Ochiai, Takanori ; Nakamura, Noriaki ; Tanaka, Hiroshi ; Anzai, Naohiko ; Sakamoto, Michiie ; Tanaka, Shinji ; Arii, Shigeki. / Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma : A prospective study. In: Journal of Gastroenterology. 2014 ; Vol. 49, No. 3. pp. 502-510.
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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).",
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AU - Matsumura, Satoshi

AU - Ban, Daisuke

AU - Irie, Takumi

AU - Ochiai, Takanori

AU - Nakamura, Noriaki

AU - Tanaka, Hiroshi

AU - Anzai, Naohiko

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AB - 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).

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