Identification of the Role of Endoplasmic Reticulum Stress Genes in Endometrial Cancer and Their Association with Tumor Immunity

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2023 Oct 25

PMID 37880674

Authors

Tang Ansu Zhang

Qian Zhang

Jun Zhang

Rong Zhao

Rui Shi

Sitian Wei

Shuangge Liu

Qi Zhang

Hongbo Wang

Affiliations

Soon will be listed here.

Abstract

Background: Endometrial cancer (EC) is one of the worldwide gynecological malignancies. Endoplasmic reticulum (ER) stress is the cellular homeostasis disturbance that participates in cancer progression. However, the mechanisms of ER Stress on EC have not been fully elucidated.

Method: The ER Stress-related genes were obtained from Gene Set Enrichment Analysis (GSEA) and GeneCards, and the RNA-seq and clinical data were downloaded from The Cancer Genome Atlas (TCGA). The risk signature was constructed by the Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis. The significance of the risk signature and clinical factors were tested by time-dependent receiver operating characteristic (ROC) curves, and the selected were to build a nomogram. The immunity correlation was particularly analyzed, including the related immune cells, pathways, and immune checkpoints. Functional enrichment, potential chemotherapies, and in vitro validation were also conducted.

Result: An ER Stress-based risk signature, consisting of TRIB3, CREB3L3, XBP1, and PPP1R15A was established. Patients were randomly divided into training and testing groups with 1:1 ratio for subsequent calculation and validation. Based on risk scores, high- and low-risk subgroups were classified, and low-risk subgroup demonstrated better prognosis. The Area Under Curve (AUC) demonstrated a reliable predictive capability of the risk signature. The majority of significantly different immune cells and pathways were enriched more in low-risk subgroup. Similarly, several typical immune checkpoints, expressed higher in low-risk subgroup. Patients of the two subgroups responded differently to chemotherapies.

Conclusion: We established an ER Stress-based risk signature that could effectively predict EC patients' prognosis and their immune correlation.

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References

Yuan Y, Jiao P, Wang Z, Chen M, Du H, Xu L . Endoplasmic reticulum stress promotes the release of exosomal PD-L1 from head and neck cancer cells and facilitates M2 macrophage polarization. Cell Commun Signal. 2022; 20(1):12. PMC: 8796490. DOI: 10.1186/s12964-021-00810-2. View

Tung H, Huang H, Lai C . Adjuvant and post-surgical treatment in endometrial cancer. Best Pract Res Clin Obstet Gynaecol. 2021; 78:52-63. DOI: 10.1016/j.bpobgyn.2021.06.002. View

Munoz-Guardiola P, Casas J, Megias-Roda E, Sole S, Perez-Montoyo H, Yeste-Velasco M . The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy. 2020; 17(6):1349-1366. PMC: 8204958. DOI: 10.1080/15548627.2020.1761651. View

Wang G, Yang Z, Zhang K . Endoplasmic reticulum stress response in cancer: molecular mechanism and therapeutic potential. Am J Transl Res. 2010; 2(1):65-74. PMC: 2826823. View

Geeleher P, Cox N, Huang R . pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One. 2014; 9(9):e107468. PMC: 4167990. DOI: 10.1371/journal.pone.0107468. View

Tierney K, Ji L, Dralla S, Yoo E, Yessaian A, Pham H . Endoplasmic reticulum stress in complex atypical hyperplasia as a possible predictor of occult carcinoma and progestin response. Gynecol Oncol. 2016; 143(3):650-654. PMC: 7474546. DOI: 10.1016/j.ygyno.2016.10.015. View

Szklarczyk D, Gable A, Nastou K, Lyon D, Kirsch R, Pyysalo S . The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2020; 49(D1):D605-D612. PMC: 7779004. DOI: 10.1093/nar/gkaa1074. View

Berger A, Korkut A, Kanchi R, Hegde A, Lenoir W, Liu W . A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. Cancer Cell. 2018; 33(4):690-705.e9. PMC: 5959730. DOI: 10.1016/j.ccell.2018.03.014. View

Ulianich L, Insabato L . Endoplasmic reticulum stress in endometrial cancer. Front Med (Lausanne). 2015; 1:55. PMC: 4291890. DOI: 10.3389/fmed.2014.00055. View

10.

Cubillos-Ruiz J, Bettigole S, Glimcher L . Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer. Cell. 2017; 168(4):692-706. PMC: 5333759. DOI: 10.1016/j.cell.2016.12.004. View

11.

Liu L, Ito S, Nishio N, Sun Y, Chen N, Tanaka Y . GADD34 Facilitates Cell Death Resulting from Proteasome Inhibition. Anticancer Res. 2015; 35(10):5317-24. View

12.

Wei W, Zhang Y, Song Q, Zhang Q, Zhang X, Liu X . Transmissible ER stress between macrophages and tumor cells configures tumor microenvironment. Cell Mol Life Sci. 2022; 79(8):403. PMC: 11073001. DOI: 10.1007/s00018-022-04413-z. View

13.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

14.

Friedman J, Hastie T, Tibshirani R . Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010; 33(1):1-22. PMC: 2929880. View

15.

Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski D . Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell. 2006; 124(3):587-99. DOI: 10.1016/j.cell.2005.11.040. View

16.

Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M . KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2022; 51(D1):D587-D592. PMC: 9825424. DOI: 10.1093/nar/gkac963. View

17.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

18.

Mahadevan N, Rodvold J, Sepulveda H, Rossi S, Drew A, Zanetti M . Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells. Proc Natl Acad Sci U S A. 2011; 108(16):6561-6. PMC: 3081038. DOI: 10.1073/pnas.1008942108. View

19.

Luo X, Alfason L, Wei M, Wu S, Kasim V . Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology. Int J Mol Sci. 2022; 23(5). PMC: 8910952. DOI: 10.3390/ijms23052746. View

20.

Luan B, Yoon Y, Le Lay J, Kaestner K, Hedrick S, Montminy M . CREB pathway links PGE2 signaling with macrophage polarization. Proc Natl Acad Sci U S A. 2015; 112(51):15642-7. PMC: 4697393. DOI: 10.1073/pnas.1519644112. View