Article Data

  • Views 503
  • Dowloads 157

Original Research

Open Access

Identification of a 3-cuproptosis-associated-lncRNA-signature that predicts the prognosis of endometrial cancer patients

  • Tianyi Liu1
  • Xinyu Wang2
  • Manyu Li3
  • Tianyu Zhu4
  • Cheng Qiu5
  • Chuhan He6
  • Lanyu Li7
  • Jinfeng Qu7,*,

1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China

2Department of Molecular Orthopaedics, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, 100035 Beijing, China

3Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong, China

4The Second Xiangya Hospital of Central South University, 410011 Changsha, Hunan, China

5Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong, China

6The Second Hospital of Shandong University, Shandong University, 250033 Jinan, Shandong, China

7Department of Obstetrics and Gynecology, Central Hospital Affiliated to Shandong First Medical University, 250013 Jinan, Shandong, China

DOI: 10.22514/ejgo.2023.073

Submitted: 20 March 2023 Accepted: 09 May 2023

Online publish date: 12 October 2023

*Corresponding Author(s): Jinfeng Qu E-mail:


Endometrial carcinoma is a common malignancy among peri-menopausal and menopausal females, even among some women of reproductive age. The treatment approach to endometrial cancer is a platinum-based regimen combined with paclitaxel, which may be unsatisfactory. A copper-mediated binding of lipoylated constituents of tricarboxylic acid cycle has been found recently, which brings about lethal protein stress and cell death, a phenomenon termed cuproptosis. As an innovative method of cell death, cuproptosis could be designed for cancer treatment and many aspects remain unaddressed. In our study, clinical, genomic, and mutational profiles of uterine corpus endometrial carcinoma (UCEC) patients were obtained from The Cancer Genome Atlas and cuproptosis-related genes and long non-coding RNAs (lncRNAs) were acquired thereafter. Co-expression and Cox regression analyses led to the development of a prognostic signature. Patients were separated into two groups (high- and low-risk groups) and survival analysis, risk score calculation, multivariate Cox analysis, and subgroup validation were implemented to determine the utility of the signature. Differentially expressed genes (DEGs) between the two groups were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Immune-related functional analysis and tumor mutation burden (TMB) analysis were performed. Three independent high-risk cuproptosis-related lncRNAs were finally confirmed and incorporated into the prognostic model, including BX322234.1, LINC01545 and LINC01224. Areas under the curve for 1-, 3- and 5-year survival were 0.717, 0.688 and 0.714, respectively. The risk model served as an independent factor to predict prognosis. Patients with high-risk and low TMB tended to have poor prognoses. Enrichment analysis demonstrated that DEGs were mostly associated with immune responses. In conclusion, the three high-risk cuproptosis-related lncRNAs could predict the prognosis of UCEC patients with higher power, where patients with high-risk and low TMB are prone to have the worst prognosis, which broadens the pattern of clinical treatment and applications.


Cuproptosis; LncRNA; Endometrial carcinoma; Prognosis; LINC01224

Cite and Share

Tianyi Liu,Xinyu Wang,Manyu Li,Tianyu Zhu,Cheng Qiu,Chuhan He,Lanyu Li,Jinfeng Qu. Identification of a 3-cuproptosis-associated-lncRNA-signature that predicts the prognosis of endometrial cancer patients. European Journal of Gynaecological Oncology. 2023.doi:10.22514/ejgo.2023.073.


[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: A Cancer Journal for Clinicians. 2021; 71: 7–33.

[2] Sung H, Ferlay J, Siegel RL, 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: A Cancer Journal for Clinicians. 2021; 71: 209–249.

[3] Colombo N, Creutzberg C, Amant F, Bosse T, González-Martín A, Ledermann J, et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Radiotherapy and Oncology. 2015; 117: 559–581.

[4] Tang D, Chen X, Kroemer G. Cuproptosis: a copper-triggered modality of mitochondrial cell death. Cell Research. 2022; 32: 417–418.

[5] Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nature Reviews Clinical Oncology. 2021; 18: 280–296.

[6] Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022; 375: 1254–1261.

[7] Ge EJ, Bush AI, Casini A, Cobine PA, Cross JR, DeNicola GM, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nature Reviews Cancer. 2022; 22: 102–113.

[8] Babak MV, Ahn D. Modulation of intracellular copper levels as the mechanism of action of anticancer copper complexes: clinical relevance. Biomedicines. 2021; 9: 852.

[9] Davis CI, Gu X, Kiefer RM, Ralle M, Gade TP, Brady DC. Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation. Metallomics. 2020; 12: 1995–2008.

[10] Polishchuk EV, Merolla A, Lichtmannegger J, Romano A, Indrieri A, Ilyechova EY, et al. Activation of autophagy, observed in liver tissues from patients with wilson disease and from ATP7B-deficient animals, protects hepatocytes from copper-induced apoptosis. Gastroenterology. 2019; 156: 1173–1189.e5.

[11] Aubert L, Nandagopal N, Steinhart Z, Lavoie G, Nourreddine S, Berman J, et al. Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer. Nature Communications. 2020; 11: 3701.

[12] Dong J, Wang X, Xu C, Gao M, Wang S, Zhang J, et al. Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson’ disease. Cell Death & Disease. 2021; 12: 87.

[13] Ren X, Li Y, Zhou Y, Hu W, Yang C, Jing Q, et al. Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis. Redox Biology. 2021; 46: 102122.

[14] Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research. 2015; 43: e47.

[15] Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. Journal of Statistical Software. 2010; 33: 1–22.

[16] Blanche P, Dartigues J, Jacqmin-Gadda H. Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks. Statistics in Medicine. 2013; 32: 5381–5397.

[17] Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. ClusterProfiler 4.0: a universal enrichment tool for interpreting omics data. The Innovation. 2021; 2: 100141.

[18] Jomova K, Makova M, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, et al. Essential metals in health and disease. Chemico-Biological Interactions. 2022; 367: 110173.

[19] Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, et al. Wilson disease. Nature Reviews Disease Primers. 2018; 4: 21.

[20] Guthrie LM, Soma S, Yuan S, Silva A, Zulkifli M, Snavely TC, et al. Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice. Science. 2020; 368: 620–625.

[21] Ge EJ, Bush AI, Casini A, Cobine PA, Cross JR, DeNicola GM, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nature Reviews Cancer. 2022; 22: 102–113.

[22] Feng Y, Zeng J, Ma Q, Zhang S, Tang J, Feng J. Serum copper and zinc levels in breast cancer: a meta-analysis. Journal of Trace Elements in Medicine and Biology. 2020; 62: 126629.

[23] Saleh SAK, Adly HM, Abdelkhaliq AA, Nassir AM. Serum levels of selenium, zinc, copper, manganese, and iron in prostate cancer patients. Current Urology. 2020; 14: 44–49.

[24] Wach S, Weigelt K, Michalke B, Lieb V, Stoehr R, Keck B, et al. Diagnostic potential of major and trace elements in the serum of bladder cancer patients. Journal of Trace Elements in Medicine and Biology. 2018; 46: 150–155.

[25] Lopez J, Ramchandani D, Vahdat L. Copper depletion as a therapeutic strategy in cancer. Metal Ions in Life Sciences. 2019; 19: 303–330.

[26] Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nature Reviews Molecular Cell Biology. 2021; 22: 266–282.

[27] Sha S, Si L, Wu X, Chen Y, Xiong H, Xu Y, et al. Prognostic analysis of cuproptosis-related gene in triple-negative breast cancer. Frontiers in Immunology. 2022; 13: 922780.

[28] Li Z, Zhang H, Wang X, Wang Q, Xue J, Shi Y, et al. Identification of cuproptosis-related subtypes, characterization of tumor microenvironment infiltration, and development of a prognosis model in breast cancer. Frontiers in Immunology. 2022; 13: 996836.

[29] Song Q, Zhou R, Shu F, Fu W. Cuproptosis scoring system to predict the clinical outcome and immune response in bladder cancer. Frontiers in Immunology. 2022; 13: 958368.

[30] Bai Y, Zhang Q, Liu F, Quan J. A novel cuproptosis-related lncRNA signature predicts the prognosis and immune landscape in bladder cancer. Frontiers in Immunology. 2022; 13: 1027449.

[31] Ding L, Li W, Tu J, Cao Z, Li J, Cao H, et al. Identification of cuproptosis-related subtypes, cuproptosis-related gene prognostic index in hepatocellular carcinoma. Frontiers in Immunology. 2022; 13: 989156.

[32] Yan C, Niu Y, Ma L, Tian L, Ma J. System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma. Journal of Translational Medicine. 2022; 20: 452.

[33] Wang T, Liu Y, Li Q, Luo Y, Liu D, Li B. Cuproptosis-related gene FDX1 expression correlates with the prognosis and tumor immune microenvironment in clear cell renal cell carcinoma. Frontiers in Immunology. 2022; 13: 999823.

[34] Pang Y, Wang Y, Zhou X, Ni Z, Chen W, Liu Y, et al. Cuproptosis-Related LncRNA-based prediction of the prognosis and immunotherapy response in papillary renal cell carcinoma. International Journal of Molecular Sciences. 2023; 24: 1464.

[35] Huang X, Zhou S, Tóth J, Hajdu A. Cuproptosis-related gene index: a predictor for pancreatic cancer prognosis, immunotherapy efficacy, and chemosensitivity. Frontiers in Immunology. 2022; 13: 978865.

[36] Liu Q, Li R, Wu H, Liang Z. A novel cuproptosis-related gene model predicts outcomes and treatment responses in pancreatic adenocarcinoma. BMC Cancer. 2023; 23: 226.

[37] Wang S, Xing N, Meng X, Xiang L, Zhang Y. Comprehensive bioinformatics analysis to identify a novel cuproptosis-related prognostic signature and its ceRNA regulatory axis and candidate traditional Chinese medicine active ingredients in lung adenocarcinoma. Frontiers in Pharmacology. 2022; 13: 971867.

[38] Chen Y, Tang L, Huang W, Zhang Y, Abisola FH, Li L. Identification and validation of a novel cuproptosis-related signature as a prognostic model for lung adenocarcinoma. Frontiers in Endocrinology. 2022; 13: 963220.

[39] Wang X, Dai C, Ye M, Wang J, Lin W, Li R. Prognostic value of an autophagy-related long-noncoding-RNA signature for endometrial cancer. Aging. 2021; 13: 5104–5119.

[40] Huo X, Wang S, Yang Q, Yu X, Gu T, Hua H, et al. Diagnostic and prognostic value of genomic instability-derived long non-coding RNA signature of endometrial cancer. Taiwanese Journal of Obstetrics and Gynecology. 2022; 61: 96–101.

[41] Li H, Gao C, Liu L, Zhuang J, Yang J, Liu C, et al. 7-lncRNA assessment model for monitoring and prognosis of breast cancer patients: based on cox regression and co-expression analysis. Frontiers in Oncology. 2019; 9: 1348.

[42] Gong A, Luo X, Tan Y, Chen H, Luo G. High expression of C10orf91 and LINC01224 in hepatocellular carcinoma and poor prognosis. American Journal of Translational Research. 2022; 14: 2567–2579.

[43] Cui Y, Zheng Y, Lu Y, Zhang M, Yang L, Li W. LINC01224 facilitates the proliferation and inhibits the radiosensitivity of melanoma cells through the miR-193a-5p/NR1D2 axis. The Kaohsiung Journal of Medical Sciences. 2022; 38: 196–206.

[44] Qiang G, Yu Q, Su K, Guo Y, Liu D, Liang C. E2F1-activated LINC01224 drives esophageal squamous cell carcinoma cell malignant behaviors via targeting miR-6884-5p/DVL3 axis and activating Wnt/β-catenin signaling pathway. Pathology—Research and Practice. 2022; 235: 153873.

[45] Gu J, Dong L, Wang Y, Nie W, Liu W, Zhao J. LINC01224 promotes colorectal cancer progression through targeting miR-485-5p/MYO6 axis. World Journal of Surgical Oncology. 2021; 19: 281.

[46] Xiao S, Sun L, Ruan B, Li J, Chen J, Xiong J, et al. Long non-coding RNA LINC01224 promotes progression and cisplatin resistance in non-small lung cancer by sponging miR-2467. Pulmonary Pharmacology & Therapeutics. 2021; 70: 102070.

[47] Sun H, Yan J, Tian G, Chen X, Song W. LINC01224 accelerates malignant transformation via MiR-193a-5p/CDK8 axis in gastric cancer. Cancer Medicine. 2021; 10: 1377–1393.

[48] Zuo X, Li W, Yan X, Ma T, Ren Y, Hua M, et al. Long non‑coding RNA LINC01224 promotes cell proliferation and inhibits apoptosis by regulating AKT3 expression via targeting miR‑485‑5p in endometrial carcinoma. Oncology Reports. 2021; 46: 186.

[49] Xu H, Zou R, Liu J, Zhu L. A risk signature with nine stemness index-associated genes for predicting survival of patients with uterine corpus endometrial carcinoma. Journal of Oncology. 2021; 2021: 1–17.

[50] Xu Z, Peng B, Liang Q, Chen X, Cai Y, Zeng S, et al. Construction of a ferroptosis-related nine-lncRNA signature for predicting prognosis and immune response in hepatocellular carcinoma. Frontiers in Immunology. 2021; 12: 719175.

Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,500 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Biological Abstracts Easily discover critical journal coverage of the life sciences with Biological Abstracts, produced by the Web of Science Group, with topics ranging from botany to microbiology to pharmacology. Including BIOSIS indexing and MeSH terms, specialized indexing in Biological Abstracts helps you to discover more accurate, context-sensitive results.

Google Scholar Google Scholar is a freely accessible web search engine that indexes the full text or metadata of scholarly literature across an array of publishing formats and disciplines.

JournalSeek Genamics JournalSeek is the largest completely categorized database of freely available journal information available on the internet. The database presently contains 39226 titles. Journal information includes the description (aims and scope), journal abbreviation, journal homepage link, subject category and ISSN.

Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.

BIOSIS Previews BIOSIS Previews is an English-language, bibliographic database service, with abstracts and citation indexing. It is part of Clarivate Analytics Web of Science suite. BIOSIS Previews indexes data from 1926 to the present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Submission Turnaround Time