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Identification of ferroptosis-related molecular subtypes and a methylation-related ferroptosis gene prognostic signature in cervical squamous cell carcinoma

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Abstract

Purpose

We aimed to investigate the molecular characteristics of cervical squamous cell carcinoma (CESC) by analyzing ferroptosis-related gene (FRG) expression data to predict prognosis.

Methods

Gene expression and clinicopathological data of patients with CESC were collected from the Cancer Genome Atlas and the Genotype-Tissue Expression databases. Using Cox regression analysis, we identified 21 FRGs associated with prognosis. Cluster analysis categorized patients into subgroups based on these genes and compared their clinicopathological, biological, and immune infiltration features. FRG methylation levels were examined, and a risk model based on such FRG methylation levels was constructed using LASSO and Cox regression analyses. The model’s predictive capacity was validated, and the relationships between the risk score and immune infiltration, tumor microenvironment, and drug sensitivity were explored. FRG methylation in CESC tissues was validated by immunohistochemistry.

Results

We identified 21 FRGs associated with CESC prognosis. Patients were stratified into two subtypes based on these genes, they showed differences in prognosis, immune cell types, and immune checkpoint expression. A three-gene risk score (including AQP3, MGST1, and TFRC) was generated, and the low-risk group showed better overall survival. The high-risk and low-risk groups differed in terms of immune infiltration, gene mutations, and drug sensitivity. Experimental validation confirmed the upregulation of AQP3 and TFRC, whereas MGST1 expression was not significantly altered in CESC tissues compared with that in normal cervical tissues.

Conclusion

This study highlights the potential role of FRG methylation in predicting CESC prognosis and provides a personalized assessment of immune responses in patients with CESC.

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Data availability

The data that support the findings of this study are available on request from the corresponding author Ping Liu, upon reasonable request.

References

  • Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y (2016) Regulators of iron homeostasis: new players in metabolism, cell death, and disease. Trends Biochem Sci 41(3):274–286

    Article  CAS  PubMed  Google Scholar 

  • Burr ML, Sparbier CE, Chan YC, Williamson JC, Woods K, Beavis PA, Lam EYN, Henderson MA, Bell CC, Stolzenburg S, Gilan O, Bloor S, Noori T, Morgens DW, Bassik MC, Neeson PJ, Behren A, Darcy PK, Dawson SJ, Voskoboinik I, Trapani JA, Cebon J, Lehner PJ, Dawson MA (2017) CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature 549(7670):101–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, Varambally S (2017) UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19(8):649–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen F, Fan Y, Hou J, Liu B, Zhang B, Shang Y, Chang Y, Cao P, Tan K (2021) Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer. Aging (albany NY) 13(17):21671–21699

    Article  CAS  PubMed  Google Scholar 

  • Cheng T, Shan G, Yang H, Gu J, Lu C, Xu F, Ge D (2022) Development of a ferroptosis-based model to predict prognosis, tumor microenvironment, and drug response for lung adenocarcinoma with weighted genes co-expression network analysis. Front Pharmacol 13:1072589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen PA, Jhingran A, Oaknin A, Denny L (2019) Cervical cancer. Lancet 393(10167):169–182

    Article  PubMed  Google Scholar 

  • Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, Zhang C, Lunceford JK, Joe A, Cheng J, Webber AL, Ibrahim N, Plimack ER, Ott PA, Seiwert TY, Ribas A, McClanahan TK, Tomassini JE, Loboda A, Kaufman D (2018) Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362(6411):eaar3593

    Article  PubMed  PubMed Central  Google Scholar 

  • Direito I, Paulino J, Vigia E, Brito MA, Soveral G (2017) Differential expression of aquaporin-3 and aquaporin-5 in pancreatic ductal adenocarcinoma. J Surg Oncol 115(8):980–996

    Article  CAS  PubMed  Google Scholar 

  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB, Liniker E, Ben K, Munhoz R, Rapisuwon S, Gherardini PF, Chmielowski B, Wang X, Shintaku IP, Wei C, Sosman JA, Joseph RW, Postow MA, Carlino MS, Hwu WJ, Scolyer RA, Messina J, Cochran AJ, Long GV, Ribas A (2018) High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553(7688):347–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Finotello F, Trajanoski Z (2018) Quantifying tumor-infiltrating immune cells from transcriptomics data. Cancer Immunol Immunother 67(7):1031–1040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao W, Wang X, Zhou Y, Wang X, Yu Y (2022) Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther 7(1):196

    Article  PubMed  PubMed Central  Google Scholar 

  • Gorvel L, Olive D (2023) Tumor associated macrophage in HPV(+) tumors: Between immunosuppression and inflammation. Semin Immunol 65:101671

    Article  CAS  PubMed  Google Scholar 

  • Guo X, Sun T, Yang M, Li Z, Li Z, Gao Y (2013) Prognostic value of combined aquaporin 3 and aquaporin 5 overexpression in hepatocellular carcinoma. Biomed Res Int 2013:206525

    Article  PubMed  PubMed Central  Google Scholar 

  • Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, Galeas J, Dhruv HD, Berens ME, Schreiber SL, McCormick F, McManus MT (2017) Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551(7679):247–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hassannia B, Vandenabeele P, Vanden Berghe T (2019) Targeting ferroptosis to iron out cancer. Cancer Cell 35(6):830–849

    Article  CAS  PubMed  Google Scholar 

  • Hellmann MD, Callahan MK, Awad MM, Calvo E, Ascierto PA, Atmaca A, Rizvi NA, Hirsch FR, Selvaggi G, Szustakowski JD, Sasson A, Golhar R, Vitazka P, Chang H, Geese WJ, Antonia SJ (2019) Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell 35(2):329

    Article  CAS  PubMed  Google Scholar 

  • Imbert C, Montfort A, Fraisse M, Marcheteau E, Gilhodes J, Martin E, Bertrand F, Marcellin M, Burlet-Schiltz O, Peredo AG, Garcia V, Carpentier S, Tartare-Deckert S, Brousset P, Rochaix P, Puisset F, Filleron T, Meyer N, Lamant L, Levade T, Ségui B, Andrieu-Abadie N, Colacios C (2020) Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1. Nat Commun 11(1):437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SW, Chun M, Ryu HS, Chang SJ, Kong TW, Lee EJ, Lee YH, Oh YT (2017) Salvage radiotherapy with or without concurrent chemotherapy for pelvic recurrence after hysterectomy alone for early-stage uterine cervical cancer. Strahlenther Onkol 193(7):534–542

    Article  PubMed  Google Scholar 

  • Kodach LL, Peppelenbosch MP (2021) Targeting the myeloid-derived suppressor cell compartment for inducing responsiveness to immune checkpoint blockade is best limited to specific subtypes of gastric cancers. Gastroenterology 161(2):727

    Article  PubMed  Google Scholar 

  • Kuang F, Liu J, Xie Y, Tang D, Kang R (2021) MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells. Cell Chem Biol 28(6):765-775.e765

    Article  CAS  PubMed  Google Scholar 

  • Li D, Li Y (2020) The interaction between ferroptosis and lipid metabolism in cancer. Signal Transduct Target Ther 5(1):108

    Article  PubMed  PubMed Central  Google Scholar 

  • Li A, Lu D, Zhang Y, Li J, Fang Y, Li F, Sun J (2013) Critical role of aquaporin-3 in epidermal growth factor-induced migration of colorectal carcinoma cells and its clinical significance. Oncol Rep 29(2):535–540

    Article  PubMed  Google Scholar 

  • Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, Sell A, Wei S, Grove S, Johnson JK, Kennedy PD, Gijón M, Shah YM, Zou W (2022) CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell 40(4):365-378.e366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Machida Y, Ueda Y, Shimasaki M, Sato K, Sagawa M, Katsuda S, Sakuma T (2011) Relationship of aquaporin 1, 3, and 5 expression in lung cancer cells to cellular differentiation, invasive growth, and metastasis potential. Hum Pathol 42(5):669–678

    Article  CAS  PubMed  Google Scholar 

  • Manolakos A, Ochoa I, Venkat K, Goldsmith AJ, Gevaert O (2014) CaMoDi: a new method for cancer module discovery. BMC Genom 15(Suppl 10):S8

    Article  Google Scholar 

  • Manz DH, Blanchette NL, Paul BT, Torti FM, Torti SV (2016) Iron and cancer: recent insights. Ann N Y Acad Sci 1368(1):149–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minion LE, Tewari KS (2018) Cervical cancer–state of the science: From angiogenesis blockade to checkpoint inhibition. Gynecol Oncol 148(3):609–621

    Article  PubMed  PubMed Central  Google Scholar 

  • Morgenstern R, Zhang J, Johansson K (2011) Microsomal glutathione transferase 1: mechanism and functional roles. Drug Metab Rev 43(2):300–306

    Article  CAS  PubMed  Google Scholar 

  • Nagase H, Ghosh S (2008) Epigenetics: differential DNA methylation in mammalian somatic tissues. Febs J 275(8):1617–1623

    Article  CAS  PubMed  Google Scholar 

  • Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ooko E, Saeed ME, Kadioglu O, Sarvi S, Colak M, Elmasaoudi K, Janah R, Greten HJ, Efferth T (2015) Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine 22(11):1045–1054

    Article  CAS  PubMed  Google Scholar 

  • Qi X, Fu Y, Sheng J, Zhang M, Zhang M, Wang Y, Li G (2021) A novel ferroptosis-related gene signature for predicting outcomes in cervical cancer. Bioengineered 12(1):1813–1825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin W, He C, Jiang D, Gao Y, Chen Y, Su M, Yang Y, Yang Z, Cai H, Wang H (2022) Systematic construction and validation of a novel ferroptosis-related gene model for predicting prognosis in cervical cancer. J Immunol Res 2022:2148215

    Article  PubMed  PubMed Central  Google Scholar 

  • Reiter JG, Baretti M, Gerold JM, Makohon-Moore AP, Daud A, Iacobuzio-Donahue CA, Azad NS, Kinzler KW, Nowak MA, Vogelstein B (2019) An analysis of genetic heterogeneity in untreated cancers. Nat Rev Cancer 19(11):639–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Small W Jr, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, Jhingran A, Kitchener HC, Mileshkin LR, Viswanathan AN, Gaffney DK (2017) Cervical cancer: a global health crisis. Cancer 123(13):2404–2412

    Article  PubMed  Google Scholar 

  • Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, Tang D (2016) Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63(1):173–184

    Article  CAS  PubMed  Google Scholar 

  • Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249

    Article  PubMed  Google Scholar 

  • Wan S, Lei Y, Li M, Wu B (2022) A prognostic model for hepatocellular carcinoma patients based on signature ferroptosis-related genes. Hepatol Int 16(1):112–124

    Article  PubMed  Google Scholar 

  • Wang J, Feng L, Zhu Z, Zheng M, Wang D, Chen Z, Sun H (2015) Aquaporins as diagnostic and therapeutic targets in cancer: how far we are? J Transl Med 13:96

    Article  PubMed  PubMed Central  Google Scholar 

  • Woloszynska-Read A, Mhawech-Fauceglia P, Yu J, Odunsi K, Karpf AR (2008) Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer. Clin Cancer Res 14(11):3283–3290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W, Wang J (2019) Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med 23(8):4900–4912

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi H, Hsu JL, Chen CT, Wang YN, Hsu MC, Chang SS, Du Y, Ko HW, Herbst R, Hung MC (2013) Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells. Clin Cancer Res 19(4):845–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Q, Al-Hendy A (2022) The regulatory functions and the mechanisms of long non-coding RNAs in cervical cancer. Cells 11(7):1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang C, Li J, Guo Y, Gan D, Zhang C, Wang R, Hua L, Zhu L, Ma P, Shi J, Li S, Su H (2022a) Role of TFRC as a novel prognostic biomarker and in immunotherapy for pancreatic carcinoma. Front Mol Biosci 9:756895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang L, Chen Z, Liu Y, Wang X, Li J, Ye Q (2022b) Immunization combined with ferroptosis related genes to construct a new prognostic model for head and neck squamous cell carcinoma. Cancers (basel) 14(17):4099

    Article  CAS  PubMed  Google Scholar 

  • Yee PP, Wei Y, Kim SY, Lu T, Chih SY, Lawson C, Tang M, Liu Z, Anderson B, Thamburaj K, Young MM, Aregawi DG, Glantz MJ, Zacharia BE, Specht CS, Wang HG, Li W (2020) Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression. Nat Commun 11(1):5424

    Article  PubMed  PubMed Central  Google Scholar 

  • Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, Treviño V, Shen H, Laird PW, Levine DA, Carter SL, Getz G, Stemke-Hale K, Mills GB, Verhaak RG (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612

    Article  PubMed  Google Scholar 

  • Yuan Z, Zhu H, Zeng P, Yang S, Sun S, Yang C, Liu J, Zhou X (2020) Testing and controlling for horizontal pleiotropy with probabilistic Mendelian randomization in transcriptome-wide association studies. Nat Commun 11(1):3861

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all quoted authors for their contributions to this work.

Funding

The research leading to these results has received no specific grant.

Author information

Author notes

  1. Lijun Yu and Zhenwei Gao contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecology, Nanfang Hospital, Southern Medical University, No. 1838, Guang Zhou Northern Avenue, Guangzhou, 510515, China

    Lijun Yu, Zhenwei Gao & Ping Liu

  2. Department of Gynecology, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, shanxi, China

    Lijun Yu & Ya Gao

  3. Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan, 030001, shanxi, China

    Zeyu Li

  4. Department of Pathology, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, shanxi, China

    Gang Liang

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  1. Lijun Yu
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  2. Zhenwei Gao
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  3. Zeyu Li
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Contributions

LY contributed to the study conception and design. Material preparation, data collection and analysis were performed by LY and ZG. YG and GL performed the experiment. LY and ZL wrote the first draft of the manuscript altogether and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ping Liu.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The study was approved by the Clinical Research Ethics Committee of the first Hospital of Shanxi Medical University.

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Freely and informed consent was obtained from all authors to participate in the study.

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Yu, L., Gao, Z., Li, Z. et al. Identification of ferroptosis-related molecular subtypes and a methylation-related ferroptosis gene prognostic signature in cervical squamous cell carcinoma. J Cancer Res Clin Oncol 149, 14673–14689 (2023). https://doi.org/10.1007/s00432-023-05267-z

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  • DOI: https://doi.org/10.1007/s00432-023-05267-z

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