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Iron overload is related to muscle wasting in patients with cachexia of gastric cancer: using quantitative proteome analysis

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Abstract

The incidence of gastric cancer cachexia is high and the clinical management is poor, so the study aimed to clarify the mechanism of muscle wasting to better screen patients with gastric cancer cachexia. Gastric cancer patients undergoing radical gastrectomy were divided into cachexia with sarcopenia (CS, n = 13) and normal (N, n = 10) two groups. The possible mechanism of skeletal muscle reduction was explored through Tandem Mass Tag (TMT) technique, Perls staining, Western blot analysis and measurement of oxidative stress indicators. The preoperative weight, weight loss, body mass index, calorie intake and skeletal muscle index values of the CS group were significantly lower than those of the N group (P < 0.05). We identified 114 differentially expressed proteins (DEP) in the muscles of two groups using TMT analysis. Bioinformatics analysis of DEP revealed that ferritin, iron and oxidative stress may be related to skeletal muscle consumption. Following Perls staining and measurement iron concentration in skeletal muscles, we found that the iron in the muscles of the CS group was significantly increased, and at the same time, western blot analysis showed that the expression of ferritin in the CS group was significantly increased and regulated by hepcidin-ferroportin axis. Finally, the CS group showed increased oxidative stress and weakened antioxidant stress systems in the muscles compared with the N group when oxidative stress indicators were analyzed. In conclusion, iron overload may be related to muscle loss in patients with gastric cancer cachexia. Gastric cancer patients with elevated ferritin are more likely to have muscle wasting.

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References

  1. Yang L, Zheng R, Wang N, Yuan Y, Liu S, Li H, et al. Incidence and mortality of stomach cancer in China, 2014. Chin J Cancer Res. 2018;30:291–8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Digklia A, Wagner AD. Advanced gastric cancer: current treatment landscape and future perspectives. World J Gastroenterol. 2016;22:2403–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sun L, Quan XQ, Yu S. An epidemiological survey of cachexia in advanced cancer patients and analysis on its diagnostic and treatment status. Nutr Cancer. 2015;67:1056–62.

    Article  PubMed  Google Scholar 

  4. Dodson S, Baracos VE, Jatoi A, Evans WJ, Cella D, Dalton JT, et al. Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies. Annu Rev Med. 2011;62:265–79.

    Article  CAS  PubMed  Google Scholar 

  5. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489–95.

    Article  PubMed  Google Scholar 

  6. Zhuang C-L, Huang D-D, Pang W-Y, Zhou C-J, Wang S-L, Lou N, et al. Sarcopenia is an independent predictor of severe postoperative complications and long-term survival after radical gastrectomy for gastric cancer. Medicine. 2016;95:e3164.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kudou K, Saeki H, Nakashima Y, Edahiro K, Korehisa S, Taniguchi D, et al. Prognostic significance of sarcopenia in patients with esophagogastric junction cancer or upper gastric cancer. Ann Surg Oncol. 2017;24:1804–10.

    Article  PubMed  Google Scholar 

  8. Mertins P, Tang LC, Krug K, Clark DJ, Gritsenko MA, Chen L, et al. Reproducible workflow for multiplexed deep-scale proteome and phosphoproteome analysis of tumor tissues by liquid chromatography-mass spectrometry. Nat Protoc. 2018;13:1632–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dev S, Babitt JL. Overview of iron metabolism in health and disease. Hemodial Int. 2017;21(Suppl 1):S6-s20.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, et al. Sarcopenia, intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma. J Hepatol. 2015;63:131–40.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang Y, Wang J, Wang X, Gao T, Tian H, Zhou D, et al. The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia. Am J Clin Nutr. 2020;111:570–9.

    Article  PubMed  Google Scholar 

  12. Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med. 2012;366:348–59.

    Article  CAS  PubMed  Google Scholar 

  13. Anderson GJ, Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr. 2017;106:1559s-s1566.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Altun M, Edstrom E, Spooner E, Flores-Moralez A, Bergman E, Tollet-Egnell P, et al. Iron load and redox stress in skeletal muscle of aged rats. Muscle Nerve. 2007;36:223–33.

    Article  CAS  PubMed  Google Scholar 

  15. Reardon TF, Allen DG. Iron injections in mice increase skeletal muscle iron content, induce oxidative stress and reduce exercise performance. Exp Physiol. 2009;94:720–30.

    Article  CAS  PubMed  Google Scholar 

  16. Ikeda Y, Imao M, Satoh A, Watanabe H, Hamano H, Horinouchi Y, et al. Iron-induced skeletal muscle atrophy involves an Akt-forkhead box O3–E3 ubiquitin ligase-dependent pathway. J Trace Elem Med Biol. 2016;35:66–76.

    Article  CAS  PubMed  Google Scholar 

  17. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–3.

    Article  CAS  PubMed  Google Scholar 

  19. Du F, Qian ZM, Gong Q, Zhu ZJ, Lu L, Ke Y. The iron regulatory hormone hepcidin inhibits expression of iron release as well as iron uptake proteins in J774 cells. J Nutr Biochem. 2012;23:1694–700.

    Article  CAS  PubMed  Google Scholar 

  20. Gu Z, Wang H, Xia J, Yang Y, Jin Z, Xu H, et al. Decreased ferroportin promotes myeloma cell growth and osteoclast differentiation. Cancer Res. 2015;75:2211–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xue D, Zhou CX, Shi YB, Lu H, He XZ. Decreased expression of ferroportin in prostate cancer. Oncol Lett. 2015;10:913–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13:342–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Yu L, Ding J, Chen Y. Iron metabolism in cancer. Int J Mol Sci. 2018;20:95.

    Article  PubMed Central  Google Scholar 

  24. Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275:161–203.

    Article  PubMed  Google Scholar 

  25. Rucker P, Torti FM, Torti SV. Role of H and L subunits in mouse ferritin. J Biol Chem. 1996;271:33352–7.

    Article  CAS  PubMed  Google Scholar 

  26. Kim TH, Hwang HJ, Kim SH. Relationship between serum ferritin levels and sarcopenia in Korean females aged 60 years and older using the fourth Korea National Health and Nutrition Examination Survey (KNHANES IV-2, 3), 2008–2009. PLoS ONE. 2014;9:e90105.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nakagawa C, Inaba M, Ishimura E, Yamakawa T, Shoji S, Okuno S. Association of increased serum ferritin with impaired muscle strength/quality in hemodialysis patients. J Ren Nutr. 2016;26:253–7.

    Article  CAS  PubMed  Google Scholar 

  28. Oberley LW, Buettner GR. Role of superoxide dismutase in cancer: a review. Cancer Res. 1979;39:1141–9.

    CAS  PubMed  Google Scholar 

  29. Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature. 2000;407:390–5.

    Article  CAS  PubMed  Google Scholar 

  30. Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 2009;30:1–12.

    Article  CAS  PubMed  Google Scholar 

  31. Tsikas D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges. Anal Biochem. 2017;524:13–30.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by National Natural Science Foundation of China (Grant No. 81770531) and Jiangsu Outstanding Youth Foundation (Grant No. BK20170009).

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Author notes

  1. Da Zhou and Ying Zhang contributed equally to this work.

Authors and Affiliations

  1. Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, People’s Republic of China

    Da Zhou, Gulsudum Mamtawla, Songlin Wan, Xuejin Gao, Li Zhang, Guoli Li & Xinying Wang

  2. Department of Cardiothoracic Surgery, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Ying Zhang

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  1. Da Zhou
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  2. Ying Zhang
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  3. Gulsudum Mamtawla
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  6. Li Zhang
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  7. Guoli Li
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Contributions

WXY and ZY designed the study. GM, WSL, GXJ, and ZL collected the samples. ZD performed the experiments. ZD and ZY analyzed the data and wrote the manuscript. WXY and LGL reviewed/edited the manuscript. WXY and LGL supervised the research. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guoli Li or Xinying Wang.

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There are no potential conflict of interest.

Research involved in human rights

The study was approved by the Ethics Committee of the Jinling hospital (Approval No. 2017NZKY-003-01).

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Zhou, D., Zhang, Y., Mamtawla, G. et al. Iron overload is related to muscle wasting in patients with cachexia of gastric cancer: using quantitative proteome analysis. Med Oncol 37, 113 (2020). https://doi.org/10.1007/s12032-020-01439-w

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