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Original Research

Open Access

Transcriptome analysis constructed the necroptosis associated prognostic signature in endometrial cancer and identified EZH2 as a potential biomarker

  • Yueying Cao1,†
  • Zhengzheng Ding1,†
  • Lizhou Sun1,*,

1Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China

DOI: 10.22514/ejgo.2023.060 Vol.44,Issue 4,August 2023 pp.83-94

Submitted: 22 November 2022 Accepted: 10 May 2023

Published: 15 August 2023

*Corresponding Author(s): Lizhou Sun E-mail:

† These authors contributed equally.


Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system, but our understanding of the tumor microenvironment of EC remains unclear. Programmed cell death (PCD) plays an important role in the genesis and progression of tumors. Necroptosis is a novel form of PCD that does not rely on the caspase system. However, the role of necroptosis in EC is unclear. Transcriptome data of endometrial cancer were downloaded from The Cancer Genome Atlas (TCGA) database and log2 conversion was performed. Expression analysis and correlation analysis were performed to explore necroptosis gene expression and interaction in EC. Lasso regression was used to construct necroptosis-related prognostic signature. Finally, immunocorrelation analysis and single cell sequencing analysis were used to explore the significance of this signature in EC tumor microenvironment. A total of 15 of the 17 necroptosis genes were differentially expressed in EC. Subsequently, necroptosis related prognostic signature was constructed through Lasso regression. Riskscore = (−0.0999) × Toll-likereceptor4 (TLR4) + (−0.0528) × tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) + (0.1208) × Enhancer of Zeste Homolog 2 (EZH2) + (−0.004) × N-myc Down-stream Regulated Gene 2 (NDRG2). EC patients can be divided into high-risk group and low-risk group based on the median riskscore and the high-risk group has a worse prognosis. Survival analysis showed a worse prognosis for patients in the high-risk group (p < 0.05). Immunomicroenvironment analysis showed a significant negative correlation between risk score and infiltration levels of B cells, CD4+ T cells, CD8+ T cells, Endothelial cells, macrophages, and NK cells. Subsequent cell experiments showed that knockdown of the key gene EZH2 in signature significantly reduced the invasion, migration and healing abilities of EC cell lines, proving that EZH2 is a promising marker of EC.


Endometrial cancer; Programmed cell death; Necroptosis; EZH2; Bioinformatics

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Yueying Cao,Zhengzheng Ding,Lizhou Sun. Transcriptome analysis constructed the necroptosis associated prognostic signature in endometrial cancer and identified EZH2 as a potential biomarker. European Journal of Gynaecological Oncology. 2023. 44(4);83-94.


[1] PDQ Screening and Prevention Editorial Board. Endometrial Cancer Prevention (PDQ®): health professional version. In: PDQ Cancer Information Summaries. National Cancer Institute (US): Bethesda (MD). 2023.

[2] King L, Gajarawala S, McCrary MD. Endometrial cancer and obesity: addressing the awkward silence. JAAPA. 2023; 36: 28–31.

[3] Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. The New England Journal of Medicine. 2022; 386: 437–448.

[4] Passarello K, Kurian S, Villanueva V. Endometrial cancer: an overview of pathophysiology, management, and care. Seminars in Oncology Nursing. 2019; 35: 157–165.

[5] Trojano G, Olivieri C, Tinelli R, Damiani GR, Pellegrino A, Cicinelli E. Conservative treatment in early stage endometrial cancer: a review. Acta Bio-Medica. 2019; 90: 405–410.

[6] Robison K, Wohlrab K, Howe CJ, Richter HE, Sung V, Bevis KS, et al. Endometrial cancer surgery with or without concomitant stress urinary incontinence surgery. Obstetrics & Gynecology. 2023; 141: 642–652.

[7] Harkenrider MM, Abu-Rustum N, Albuquerque K, Bradfield L, Bradley K, Dolinar E, et al. Radiation therapy for endometrial cancer: an American society for radiation oncology clinical practice guideline. Practical Radiation Oncology. 2023; 13: 41–65.

[8] Brooks RA, Fleming GF, Lastra RR, Lee NK, Moroney JW, Son CH, et al. Current recommendations and recent progress in endometrial cancer. CA: A Cancer Journal for Clinicians. 2019; 69: 258–279.

[9] Connor EV, Rose PG. Management strategies for recurrent endometrial cancer. Expert Review of Anticancer Therapy. 2018; 18: 873–885.

[10] Di Tucci C, Capone C, Galati G, Iacobelli V, Schiavi MC, Di Donato V, et al. Immunotherapy in endometrial cancer: new scenarios on the horizon. Journal of Gynecologic Oncology. 2019; 30: e46.

[11] Eskander RN, Sill MW, Beffa L, Moore RG, Hope JM, Musa FB, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. The New England Journal of Medicine. 2023. [Preprint].

[12] Arend RC, Jones BA, Martinez A, Goodfellow P. Endometrial cancer: molecular markers and management of advanced stage disease. Gynecologic Oncology. 2018; 150: 569–580.

[13] Cassetta L, Fragkogianni S, Sims AH, Swierczak A, Forrester LM, Zhang H, et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell. 2019; 35: 588–602.e10.

[14] Elmore S. Apoptosis: a review of programmed cell death. Toxicologic Pathology. 2007; 35: 495–516.

[15] Nagata S, Tanaka M. Programmed cell death and the immune system. Nature Reviews Immunology. 2017; 17: 333–340.

[16] Mirgayazova R, Khadiullina R, Mingaleeva R, Chasov V, Gomzikova M, Garanina E, et al. Novel Isatin-based activator of p53 transcriptional functions in tumor cells. Molecular Biology Research Communications. 2019; 8: 119–128.

[17] Mishra AP, Salehi B, Sharifi-Rad M, Pezzani R, Kobarfard F, Sharifi-Rad J, et al. Programmed cell death, from a cancer perspective: an overview. Molecular Diagnosis & Therapy. 2018; 22: 281–295.

[18] Constantinou C, Papas K, Constantinou A. Caspase-independent pathways of programmed cell death: the unraveling of new targets of cancer therapy? Current Cancer Drug Targets. 2009; 9: 717–728.

[19] Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death & Differentiation. 2019; 26: 99–114.

[20] Wooller S, Benstead-Hume G, Chen X, Ali Y, Pearl FG. Bioinformatics in translational drug discovery. Bioscience Reports. 2017; 37: BSR20160180.

[21] Xie J, Chen L, Cao Y, Wu D, Xiong W, Zhang K, et al. Single-cell sequencing analysis and weighted co-expression network analysis based on public databases identified that TNC is a novel biomarker for keloid. Frontiers in Immunology. 2021; 12: 783907.

[22] Cao Y, Xie J, Chen L, Hu Y, Zhai L, Yuan J, et al. Construction and validation of a novel Pyroptosis-related gene signature to predict the prognosis of uveal melanoma. Frontiers in Cell and Developmental Biology. 2021; 9: 761350.

[23] Xu Y, Wu D, Hui B, Shu L, Tang X, Wang C, et al. A novel regulatory mechanism network mediated by lncRNA TUG1 that induces the impairment of spiral artery remodeling in preeclampsia. Molecular Therapy. 2022; 30: 1692–1705.

[24] Xu Y, Ge Z, Zhang E, Zuo Q, Huang S, Yang N, et al. The lncRNA TUG1 modulates proliferation in trophoblast cells via epigenetic suppression of RND3. Cell Death & Disease. 2017; 8: e3104.

[25] Moore K, Brewer MA. Endometrial cancer: is this a new disease?American Society of Clinical Oncology Educational Book. 2017; 37: 435–442.

[26] Hutt S, Tailor A, Ellis P, Michael A, Butler-Manuel S, Chatterjee J. The role of biomarkers in endometrial cancer and hyperplasia: a literature review. Acta Oncologica. 2019; 58: 342–352.

[27] Son J, Carr C, Yao M, Radeva M, Priyadarshini A, Marquard J, et al. Endometrial cancer in young women: prognostic factors and treatment outcomes in women aged ≤40 years. International Journal of Gynecologic Cancer. 2020; 30: 631–639.

[28] Urick ME, Bell DW. Clinical actionability of molecular targets in endometrial cancer. Nature Reviews Cancer. 2019; 19: 510–521.

[29] Vermij L, Smit V, Nout R, Bosse T. Incorporation of molecular characteristics into endometrial cancer management. Histopathology. 2020; 76: 52–63.

[30] Bell DW, Ellenson LH. Molecular genetics of endometrial carcinoma. Annual Review of Pathology. 2019; 14: 339–367.

[31] Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma: more than two types. The Lancet Oncology. 2014; 15: e268–e278.

[32] Dai X, Wang D, Zhang J. Programmed cell death, redox imbalance, and cancer therapeutics. Apoptosis. 2021; 26: 385–414.

[33] Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nature Reviews Clinical Oncology. 2020; 17: 395–417.

[34] Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D’Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging. 2016; 8: 603–619.

[35] Ke B, Tian M, Li J, Liu B, He G. Targeting programmed cell death using small-molecule compounds to improve potential cancer therapy. Medicinal Research Reviews. 2016; 36: 983–1035.

[36] Sun Y, Peng ZL. Programmed cell death and cancer. Postgraduate Medical Journal. 2009; 85: 134–140.

[37] Baik JY, Liu Z, Jiao D, Kwon HJ, Yan J, Kadigamuwa C, et al. ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer. Nature Communications. 2021; 12: 2666.

[38] Xie Y, Zhao Y, Shi L, Li W, Chen K, Li M, et al. Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer. The Journal of Clinical Investigation. 2020; 130: 2111–2128.

[39] Xie J, Chen L, Tang Q, Wei W, Cao Y, Wu C, et al. A necroptosis-related prognostic model of uveal melanoma was constructed by single-cell sequencing analysis and weighted co-expression network analysis based on public databases. Frontiers in Immunology. 2022; 13: 847624.

[40] Gui T, Liu M, Yao B, Jiang H, Yang D, Li Q, et al. TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer. Cell Death & Differentiation. 2021; 28: 3316–3328.

[41] Ihira K, Dong P, Xiong Y, Watari H, Konno Y, Hanley SJ, et al. ZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. Oncotarget. 2017; 8: 13509–13520.

[42] Oki S, Sone K, Oda K, Hamamoto R, Ikemura M, Maeda D, et al. Oncogenic histone methyltransferase EZH2: a novel prognostic marker with therapeutic potential in endometrial cancer. Oncotarget. 2017; 8: 40402–40411.

[43] Weijiao Y, Fuchun L, Mengjie C, Xiaoqing Q, Hao L, Yuan L, et al. Immune infiltration and a ferroptosis-associated gene signature for predicting the prognosis of patients with endometrial cancer. Aging. 2021; 13: 16713–16732.

[44] Chen Y, Liao Y, Du Q, Shang C, Qin S, Lee K, et al. Roles of pyroptosis-related gene signature in prediction of endometrial cancer outcomes. Frontiers in Medicine. 2022; 9: 822806.

[45] Liang D, Hu M, Tang Q, Huang M, Tang L. Nine Pyroptosis-related lncRNAs are identified as biomarkers for predicting the prognosis and immunotherapy of endometrial carcinoma. International Journal of General Medicine. 2021; 14: 8073–8085.

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