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Overexpression of ferroptosis-related genes FSP1 and CISD1 is related to prognosis and tumor immune infiltration in gastric cancer

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Abstract

Purpose

Gastric cancer (GC) is one of the highest incidence rate cancers worldwide and the search for new biomarkers remains urgent due to its relatively poor prognosis and limited treatment methods. Ferroptosis suppressor protein 1 (FSP1) and iron sulfur domain 1 (CISD1) promoted malignant tumor progression as ferroptosis suppressors in a variety of tumors, but their study in GC remains to be explored.

Methods

In our study, FSP1 and CISD1 expression were predicted through different databases and confirmed by qRT-PCR, immunohistochemistry and western blotting. Enrichment analyses were exploited to explore the potential functions of FSP1 and CISD1. Finally, their relationship with immune infiltration was determined by Tumor Immune Estimation Resource and ssGSEA algorithm.

Results

The expression of FSP1 and CISD1 was higher in GC tissues. Their strongly positive immunostaining was associated with increased tumor size, degree of differentiation, depth of invasion and lymph node metastasis in GC patients. Up-regulated FSP1 and CISD1 predicted poorer overall survival of patients with GC. Furthermore, FSP1 and CISD1 as ferroptosis inhibitors were predicted to be involved in GC immune cell infiltration.

Conclusions

Our study suggested that FSP1 and CISD1 acted as biomarkers of poor prognosis and promising immunotherapeutic targets for GC.

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Data availability

The data generated and analyzed in this study were available.

References

  1. Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020 GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Gotoda T. Endoscopic resection of early gastric cancer. Gastric Cancer. 2007;10:1–11.

    Article  PubMed  Google Scholar 

  3. Wu M, Xu LG, Li X, Zhai Z, Shu HB. AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis. J Biol Chem. 2002;277:25617–23.

    Article  CAS  PubMed  Google Scholar 

  4. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Koppula P, Lei G, Zhang Y, Yan Y, Mao C, Kondiparthi L, et al. A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat Commun. 2022;13:2206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dai E, Zhang W, Cong D, Kang R, Wang J, Tang D. AIFM2 blocks ferroptosis independent of ubiquinol metabolism. Biochem Biophys Res Commun. 2020;523:966–71.

    Article  CAS  PubMed  Google Scholar 

  7. Wiley SE, Murphy AN, Ross SA, van der Geer P, Dixon JE. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. Proc Natl Acad Sci U S A. 2007;104:5318–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yuan H, Li X, Zhang X, Kang R, Tang D. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem Biophys Res Commun. 2016;478:838–44.

    Article  CAS  PubMed  Google Scholar 

  9. Sohn YS, Tamir S, Song L, Michaeli D, Matouk I, Conlan AR, et al. NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth. Proc Natl Acad Sci U S A. 2013;110:14676–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jiang X, Yuan Y, Tang L, Wang J, Zhang D, Duan L. Systematic analysis and validation of the prognosis, immunological role and biology function of the ferroptosis-related lncRNA GSEC/miRNA-101-3p/CISD1 axis in lung adenocarcinoma. Front Mol Biosci. 2021;8: 793732.

    Article  CAS  PubMed  Google Scholar 

  11. Yang Y, Hu H, Chen L, Zhang H, Yang J. A new survival model based on ferroptosis-related genes (FRGS) for prognostic prediction in bladder cancer. Actas Urol Esp (Engl Ed). 2022;46:494–503.

    Article  PubMed  Google Scholar 

  12. Song Y, Tian S, Zhang P, Zhang N, Shen Y, Deng J. Construction and validation of a novel ferroptosis-related prognostic model for acute myeloid leukemia. Front Genet. 2021;12: 708699.

    Article  CAS  PubMed  Google Scholar 

  13. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 2019;10:1617.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gao W, Wang X, Zhou Y, Wang X, Yu Y. Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther. 2022;7:196.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tang B, Xu W, Wang Y, Zhu J, Wang H, Tu J, et al. Identification of critical ferroptosis regulators in lung adenocarcinoma that RRM2 facilitates tumor immune infiltration by inhibiting ferroptotic death. Clin Immunol. 2021;232: 108872.

    Article  CAS  PubMed  Google Scholar 

  17. Fan F, Liu P, Bao R, Chen J, Zhou M, Mo Z, et al. A Dual PI3K/HDAC inhibitor induces immunogenic ferroptosis to potentiate cancer immune checkpoint therapy. Cancer Res. 2021;81:6233–45.

    Article  CAS  PubMed  Google Scholar 

  18. Yang J, Jia Z, Zhang J, Pan X, Wei Y, Ma S, et al. Metabolic intervention nanoparticles for triple-negative breast cancer therapy via overcoming FSP1-mediated ferroptosis resistance. Adv Healthc Mater. 2022;11: e2102799.

    Article  PubMed  Google Scholar 

  19. Luo H, Ma C. A Novel ferroptosis-associated gene signature to predict prognosis in patients with uveal melanoma. Diagnostics (Basel). 2021;11:219.

    Article  CAS  PubMed  Google Scholar 

  20. Shi ZZ, Tao H, Fan ZW, Song SJ, Bai J. Prognostic and immunological role of key genes of ferroptosis in pan-cancer. Front Cell Dev Biol. 2021;9: 748925.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lu T, Li C, Xiang C, Gong Y, Peng W, Chen C. Overexpression of CISD1 predicts worse survival in hepatocarcinoma patients. Biomed Res Int. 2022;2022:7823191.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wu ZH, Tang Y, Yu H, Li HD. The role of ferroptosis in breast cancer patients: a comprehensive analysis. Cell Death Discov. 2021;7:93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu Y, Xu Z, Jin T, Xu K, Liu M, Xu H. Ferroptosis in low-grade glioma: a new marker for diagnosis and prognosis. Med Sci Monit. 2020;26: e921947.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hao S, Yu J, He W, Huang Q, Zhao Y, Liang B, et al. Cysteine dioxygenase 1 mediates erastin-induced ferroptosis in human gastric cancer cells. Neoplasia. 2017;19:1022–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stauch KL, Villeneuve LM, Totusek S, Lamberty B, Ciborowski P, Fox HS. Quantitative proteomics of presynaptic mitochondria reveal an overexpression and biological relevance of neuronal MitoNEET in postnatal brain development. Dev Neurobiol. 2019;79:370–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hua J, Gao Z, Zhong S, Wei B, Zhu J, Ying R. CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1. Biochem Biophys Res Commun. 2021;577:80–8.

    Article  CAS  PubMed  Google Scholar 

  29. Wang S, Chen S, Ying Y, Ma X, Shen H, Li J, et al. Comprehensive analysis of ferroptosis regulators with regard to PD-L1 and immune infiltration in clear cell renal cell carcinoma. Front Cell Dev Biol. 2021;9: 676142.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by China Postdoctoral Science Foundation [2020M681689], The Jiangsu Planned Projects for Postdoctoral Research Funds [2021K283B], The Nantong Science and Technology Project [MS12021001] and The Nantong Commission of Health Project [MA2021001].

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Author notes

  1. Jiayi Zang and Ming Cui have contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China

    Jiayi Zang, Ming Cui, Lin Xiao & Rongrong Jing

  2. Department of Laboratory Medicine, Affiliated Rudong Hospital of Nantong University, Nantong, 226001, China

    Jianzhong Zhang

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  1. Jiayi Zang
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  2. Ming Cui
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  3. Lin Xiao
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Contributions

JZ and MC performed database analysis, experimental validation and drafted the manuscript. LX made additional revisions to the manuscript. RJ and JZ provided guidance for the study. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Jianzhong Zhang or Rongrong Jing.

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All authors claimed to have no competing interests to disclose.

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This study was approved by the Ethics committee of Affiliated Hospital of Nantong University.

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Zang, J., Cui, M., Xiao, L. et al. Overexpression of ferroptosis-related genes FSP1 and CISD1 is related to prognosis and tumor immune infiltration in gastric cancer. Clin Transl Oncol 25, 2532–2544 (2023). https://doi.org/10.1007/s12094-023-03136-2

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