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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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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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Abbreviations

CI:

Confidence interval

FDR:

False discovery rate

GSEA:

Gene set enrichment analysis

HCC:

Hepatocellular carcinoma

HR:

Hazard ratio

MO:

Multicentric occurrence

NES:

Normalized enrichment score

OR:

Odds ratio

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Acknowledgments

This work was supported by a Health and Labour Sciences Research Grant (H20-Kanen-Ippan-001) from the Ministry of Health, Labour, and Welfare of Japan and a Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors thank Hiromi Ohnari and Ayumi Shioya for clerical and technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  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

    Atsushi Kudo, Satoshi Matsumura, Daisuke Ban, Takumi Irie, Takanori Ochiai, Noriaki Nakamura, Shinji Tanaka & Shigeki Arii

  2. Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Kaoru Mogushi & Hiroshi Tanaka

  3. Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan

    Tadatoshi Takayama

  4. Department of Pathology, Graduate School of Medicine, Keio University, Tokyo, Japan

    Michiie Sakamoto

  5. Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, 321-0293, Japan

    Naohiko Anzai

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  1. Atsushi Kudo
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  2. Kaoru Mogushi
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Corresponding author

Correspondence to Atsushi Kudo.

Additional information

Accession number of repository for expression microarray data: GSE40873.

Electronic supplementary material

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Supplementary material 1 (DOC 111 kb)

535_2013_791_MOESM2_ESM.tif

Supplementary figure. 1 Sirtuin 3 related mechanisms and the correlation between SLC22A7 transports and mitochondrial mechanisms. Note the orotic acid regulated by sirtuin 3 is transported through SLC22A7. Sirtuin 3 regulates antioxidant pathway, acetate metabolism, and beta-oxidation. (TIFF 3085 kb)

535_2013_791_MOESM3_ESM.eps

Supplementary figure 2. GSEA evaluation of gene-expression profile associated with SLC22A7. Heat map of genes in the sirtuin 3-related gene set. (EPS 894 kb)

535_2013_791_MOESM4_ESM.tif

Supplementary figure 3. GSEA evaluation of gene-expression profile associated with SLC22A7. Note the enrichment plot of sirtuin 3 related gene set (P = 0.008; FDR = 0.008; NES = 1.786). (TIFF 3924 kb)

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Kudo, A., Mogushi, K., Takayama, T. et al. Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma: a prospective study. J Gastroenterol 49, 502–510 (2014). https://doi.org/10.1007/s00535-013-0791-4

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  • DOI: https://doi.org/10.1007/s00535-013-0791-4

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