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Decreased expression of the mitochondrial metabolic enzyme aconitase (ACO2) is associated with poor prognosis in gastric cancer

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Abstract

Alterations in energy metabolism play a major role in cancer development. Aconitase (ACO2) is an essential enzyme located in the mitochondria and catalyzes the interconversion of citrate and isocitrate in the tricarboxylic acid cycle. Recent studies suggest that the expression of ACO2 may be altered in certain types of cancer. The purpose of this study was to examine ACO2 expression in clinical tumor specimens from patients with gastric cancer and to evaluate the clinical relevance of ACO2 expression in gastric cancer. A total of 456 paraffin-embedded gastric cancer tissues and 30 pairs of freshly frozen tissues were used in this study. Real-time quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemical staining were performed to measure ACO2 expression in tumor tissues and matched adjacent non-tumorous tissues. The results showed that the expression of ACO2 was significantly down-regulated in gastric cancer tissues compared with matched adjacent non-tumorous tissues and was associated with clinical stage (p = 0.001), T classification (p = 0.027), N classification (p = 0.012), M classification (p = 0.002), and pathological differentiation states (p = 0.036). Patients with lower ACO2 expression had a shorter survival time than those with higher ACO2 expression. Univariate and multivariate analyses indicated that ACO2 expression functions as an independent prognostic factor (p < 0.001). Our data suggested that ACO2 could play an important role in gastric cancer and may potentially serve as a prognostic biomarker.

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References

  1. Danaei G, Vander Hoorn S, Lopez AD, Murray CJ, Ezzati M. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005;366(9499):1784–93.

    Article  PubMed  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.

    Article  PubMed  Google Scholar 

  3. Nagini S. Carcinoma of the stomach: a review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 2012;4(7):156–69.

    Article  PubMed  Google Scholar 

  4. Yasui W, Oue N, Aung PP, Matsumura S, Shutoh M, Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer. 2005;8(2):86–94.

    Article  PubMed  CAS  Google Scholar 

  5. Chen CN, Lin JJ, Chen JJ, Lee PH, Yang CY, Kuo ML, et al. Gene expression profile predicts patient survival of gastric cancer after surgical resection. J Clin Oncol. 2005;23(29):7286–95.

    Article  PubMed  CAS  Google Scholar 

  6. Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong JM, Fukayama M, et al. Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res. 2002;62(1):233–40.

    PubMed  CAS  Google Scholar 

  7. Lee HS, Cho SB, Lee HE, Kim MA, Kim JH, Park do J, et al. Protein expression profiling and molecular classification of gastric cancer by the tissue array method. Clin Cancer Res. 2007;13(14):4154–63.

    Article  PubMed  CAS  Google Scholar 

  8. Beinert H, Kennedy MC. Aconitase, a two-faced protein: enzyme and iron regulatory factor. FASEB J. 1993;7(15):1442–9.

    PubMed  CAS  Google Scholar 

  9. Gruer MJ, Artymiuk PJ, Guest JR. The aconitase family: three structural variations on a common theme. Trends Biochem Sci. 1997;22(1):3–6.

    Article  PubMed  CAS  Google Scholar 

  10. Robbins AH, Stout CD. Structure of activated aconitase: formation of the [4Fe–4S] cluster in the crystal. Proc Natl Acad Sci USA. 1989;86(10):3639–43.

    Article  PubMed  CAS  Google Scholar 

  11. Haile DJ, Rouault TA, Tang CK, Chin J, Harford JB, Klausner RD. Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster. Proc Natl Acad Sci USA. 1992;89(16):7536–40.

    Article  PubMed  CAS  Google Scholar 

  12. Tong WH, Rouault TA. Metabolic regulation of citrate and iron by aconitase: role of iron-sulfur cluster biogenesis. Biometals. 2007;20(3–4):549–64.

    Article  PubMed  CAS  Google Scholar 

  13. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  PubMed  CAS  Google Scholar 

  14. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.

    Article  PubMed  CAS  Google Scholar 

  15. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124(3215):269–70.

    PubMed  CAS  Google Scholar 

  16. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–82.

    Article  PubMed  CAS  Google Scholar 

  17. Semenza GL. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 2009;19(1):12–6.

    Article  PubMed  CAS  Google Scholar 

  18. Cai Z, Zhao JS, Li JJ, Peng DN, Wang XY, Chen TL, et al. A combined proteomics and metabolomics profiling of gastric cardia cancer reveals characteristic dysregulations in glucose metabolism. Mol Cell Proteomics. 2010;9(12):2617–28.

    Article  PubMed  CAS  Google Scholar 

  19. Laiho P, Hienonen T, Mecklin JP, Jarvinen H, Karhu A, Launonen V, et al. Mutation and LOH analysis of ACO2 in colorectal cancer: no evidence of biallelic genetic inactivation. J Med Genet. 2003;40(5):e73.

    Article  PubMed  CAS  Google Scholar 

  20. Bota DA, Davies KJ. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat Cell Biol. 2002;4(9):674–80.

    Article  PubMed  CAS  Google Scholar 

  21. Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991;51(3):794–8.

    PubMed  CAS  Google Scholar 

  22. Toyokuni S, Okamoto K, Yodoi J, Hiai H. Persistent oxidative stress in cancer. FEBS Lett. 1995;358(1):1–3.

    Article  PubMed  CAS  Google Scholar 

  23. Chen XJ, Wang X, Butow RA. Yeast aconitase binds and provides metabolically coupled protection to mitochondrial DNA. Proc Natl Acad Sci USA. 2007;104(34):13738–43.

    Article  PubMed  CAS  Google Scholar 

  24. Shadel GS, Mitochondrial DNA. aconitase ‘wraps’ it up. Trends Biochem Sci. 2005;30(6):294–6.

    Article  PubMed  CAS  Google Scholar 

  25. Chen XJ, Wang X, Kaufman BA, Butow RA. Aconitase couples metabolic regulation to mitochondrial DNA maintenance. Science. 2005;307(5710):714–7.

    Article  PubMed  CAS  Google Scholar 

  26. Sudarshan S, Sourbier C, Kong HS, Block K, Valera Romero VA, Yang Y, et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1 alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol. 2009;29(15):4080–90.

    Article  PubMed  CAS  Google Scholar 

  27. Bi X, Lin Q, Foo TW, Joshi S, You T, Shen HM, et al. Proteomic analysis of colorectal cancer reveals alterations in metabolic pathways: mechanism of tumorigenesis. Mol Cell Proteomics. 2006;5(6):1119–30.

    Article  PubMed  CAS  Google Scholar 

  28. Robey IF, Stephen RM, Brown KS, Baggett BK, Gatenby RA, Gillies RJ. Regulation of the Warburg effect in early-passage breast cancer cells. Neoplasia. 2008;10(8):745–56.

    PubMed  CAS  Google Scholar 

  29. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18(1):54–61.

    Article  PubMed  CAS  Google Scholar 

  30. Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by research grants from National Natural Science Foundation of China (No. 81101520) and from National Basic Research Program (973 Program Grant 2012CB967004).

Conflict of interest

The authors have declared no conflicts of interest.

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Authors and Affiliations

  1. State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Peng Wang, Cong Mai, Jing-jing Zhao, Yu-min Hu, Zhao-lei Zeng, Jing Yang, Wen-hua Lu, Rui-hua Xu & Peng Huang

  2. Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Cong Mai

  3. The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China

    Yong-li Wei

  4. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Rui-hua Xu

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  1. Peng Wang
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  10. Peng Huang
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Correspondence to Peng Huang.

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Peng Wang, Cong Mai, and Yong-li Wei equally contributed to this manuscript.

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Wang, P., Mai, C., Wei, Yl. et al. Decreased expression of the mitochondrial metabolic enzyme aconitase (ACO2) is associated with poor prognosis in gastric cancer. Med Oncol 30, 552 (2013). https://doi.org/10.1007/s12032-013-0552-5

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