Prognostic Assessment and Analysis of Underlying Biological Mechanisms of Prostate Cancer Based on Estrogen-Related Genes

Abstract

Prostate cancer (PCa) ranks among the most prevalent cancers in men, noted for its high mortality rate and unfavorable prognosis. Estrogen-related genes (ERGs) are significantly associated with the progression of PCa. This investigation aims to comprehensively assess the prognosis of PCa based on ERGs and explore its underlying biological mechanisms. Univariate, multivariate, and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were conducted to identify prognostic signature genes and build a prognostic model. The model’s predictive performance was assessed using Receiver Operating Characteristic (ROC) curve analysis. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed to investigate the underlying molecular mechanisms of PCa. Antitumor drugs with high sensitivity were predicted using the CellMiner database and the pRRophitic package. Additionally, miRNAs targeting the identified signature genes were predicted using the miRNet database. This study identified six ERGs as prognostic biomarkers for PCa: POU4F1, BMP2, PGF, GAS1, GNAZ, and FGF11. The findings indicated that individuals in the low-risk category exhibited improved prognostic results. Notably, PCa progression may be closely linked to the cell adhesion molecule pathway and epigenetic regulation. Additionally, hsa-let-7a-5p and hsa-miR-34a-5p were identified as potential therapeutic regulators for PCa treatment. In conclusion, this research offers novel perspectives into the progression of PCa, providing robust scientific support for the development of personalized treatment strategies for PCa patients.

Keywords

prostate cancer - estrogen-related genes - prognosis - risk model

Publication History

Received: 07 December 2024

Accepted after revision: 18 February 2025

Article published online:
10 April 2025

• References

• 1 Sekhoacha M, Riet K, Motloung P. et al. Prostate cancer review: genetics, diagnosis, treatment options, and alternative approaches. Molecules 2022; 27: 5730
• 2 Schaeffer EM, Srinivas S, Adra N. et al. Prostate cancer, Version 4.2023, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Network 2023; 21: 1067-1096
• 3 Ju W, Zheng R, Zhang S. et al. Cancer statistics in Chinese older people, 2022: current burden, time trends, and comparisons with the US, Japan, and the Republic of Korea. Sci China Life Sci 2023; 66: 1079-1091
• 4 Termini D, Den Hartogh DJ, Jaglanian A. et al. Curcumin against prostate cancer: current evidence. Biomolecules 2020; 10: 1536
• 5 Williams IS, McVey A, Perera S. et al. Modern paradigms for prostate cancer detection and management. Med J Australia 2022; 217: 424-433
• 6 Schatten H. Brief overview of prostate cancer statistics, grading, diagnosis and treatment strategies. Adv Exp Med Biol 2018; 1095: 1-14
• 7 Chen H, Pang B, Zhou C. et al. Prostate cancer-derived small extracellular vesicle proteins: the hope in diagnosis, prognosis, and therapeutics. J Nanobiotechnol 2023; 21: 480
• 8 Rebello RJ, Oing C, Knudsen KE. et al. Prostate cancer. Nat Rev Dis Primers 2021; 7: 9
• 9 Kobayashi K, Chikazawa S, Chen Y. et al. Oestrogen inhibits psoriasis-like dermatitis induced by imiquimod in mice in relation to increased IL-10 producing cells despite elevated expression of IL-22, IL-23, IL-17 mRNA. Exp Dermatol 2023; 32: 203-209
• 10 Singh JA, Shah NP, Mudano AS. Belimumab for systemic lupus erythematosus. Cochrane Database System Rev 2021; 2: Cd010668
• 11 Sakamoto T, Matsuura TR, Wan S. et al. A critical role for estrogen-related receptor signaling in cardiac maturation. Circ Res 2020; 126: 1685-1702
• 12 Lin M, Du T, Tang X. et al. An estrogen response-related signature predicts response to immunotherapy in melanoma. Front Immunol 2023; 14: 1109300
• 13 Coelingh Bennink HJT, Krijgh J, Egberts JFM. et al. Maintaining bone health by estrogen therapy in patients with advanced prostate cancer: a narrative review. Endocr Connect 2022; 11: e220182
• 14 Lafront C, Germain L, Weidmann C. et al. A systematic study of the impact of estrogens and selective estrogen receptor modulators on prostate cancer cell proliferation. Sci Rep 2020; 10: 4024
• 15 Boibessot C, Toren P. Sex steroids in the tumor microenvironment and prostate cancer progression. Endocr Relat Cancer 2018; 25: R179-R196
• 16 Lafront C, Germain L, Campolina-Silva GH. et al. The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression. J Clin Invest 2024; 134: e170809
• 17 Sarwar M, Syed Khaja AS, Aleskandarany M. et al. The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor. Oncogene 2019; 38: 375-389
• 18 Zheng Y, Weng X, Hu D. et al. Identification of a signature based on non-apoptotic regulatory cell death to improve prognosis prediction in acute myeloid leukaemia. Br J Haematol 2023; 201: 95-105
• 19 Chen Y, Chen L, Lun ATL. et al. edgeR v4: powerful differential analysis of sequencing data with expanded functionality and improved support for small counts and larger datasets. Nucleic Acid Res 2025; 53: gkaf018
• 20 Zhang H, Meltzer P, Davis S. R Circos: an R package for Circos 2D track plots. BMC Bioinform 2013; 14: 244
• 21 Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Statist Software 2010; 33: 1-22
• 22 Blanche P, Dartigues JF, Jacqmin-Gadda H. Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks. Statist Med 2013; 32: 5381-5397
• 23 Yu G. Thirteen years of clusterProfiler. Innovation [Cambridge (Mass.)] 2024; 5: 100722
• 24 Newman AM, Liu CL, Green MR. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Meth 2015; 12: 453-457
• 25 Becht E, Giraldo NA, Lacroix L. et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol 2016; 17: 218
• 26 Skidmore ZL, Wagner AH, Lesurf R. et al. GenVisR: genomic visualizations in R. Bioinformatics (Oxford, England) 2016; 32: 3012-3014
• 27 Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PloS One 2014; 9: e107468
• 28 Lowrance W, Dreicer R, Jarrard DF. et al. Updates to advanced prostate cancer: AUA/SUO guideline (2023). J Urol 2023; 209: 1082-1090
• 29 Valcarcel-Jimenez L, Macchia A, Crosas-Molist E. et al. PGC1α suppresses prostate cancer cell invasion through ERRα transcriptional control. Cancer Res 2019; 79: 6153-6165
• 30 Spirina LV, Kovaleva IV, Usynin EA. et al. Progesterone receptor expression in the benign prostatic hyperplasia and prostate cancer tissues, relation with transcription, growth factors, hormone reception and components of the AKT/mTOR signaling athway. Asian Pacific J Cancer Prevent 2020; 21: 423-429
• 31 Li TT, Lai YW, Han X. et al. BMP2 as a promising anticancer approach: functions and molecular mechanisms. Invest New Drugs 2022; 40: 1322-1332
• 32 Unterleuthner D, Neuhold P, Schwarz K. et al. Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer. Angiogenesis 2020; 23: 159-177
• 33 Bilodeau JF, Gevariya N, Larose J. et al. Long chain omega-3 fatty acids and their oxidized metabolites are associated with reduced prostate tumor growth. Prostaglandins Leukot Essent Fatty Acids 2021; 164: 102215
• 34 Chen S, Fan L, Lin Y. et al. Bifidobacterium adolescentis orchestrates CD143(+) cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1. Cancer Commun (London, England) 2023; 43: 1027-1047
• 35 Xiong Z, Ge Y, Xiao J. et al. GAS1RR, an immune-related enhancer RNA, is related to biochemical recurrence-free survival in prostate cancer. Exp Biol Med (Maywood, N.J.) 2023; 248: 1-13
• 36 Tian F, Cai D. Overexpressed GNAZ predicts poor outcome and promotes G0/G1 cell cycle progression in hepatocellular carcinoma. Gene 2022; 807: 145964
• 37 Hu S, Li L, Yeh S. et al. Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling. Mol Oncol 2015; 9: 44-57
• 38 Kaur J, Daoud A, Eblen ST. Targeting chromatin remodeling for cancer therapy. Curr Mol Pharmacol 2019; 12: 215-229
• 39 Smith IR, Hendricks EL, Latcheva NK. et al. The CHD protein kismet restricts the synaptic localization of cell adhesion molecules at the Drosophila neuromuscular junction. Int J Mol Sci 2024; 25: 3074
• 40 Beauchemin N, Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 2013; 32: 643-671
• 41 Mason MD, Davies G, Jiang WG. Cell adhesion molecules and adhesion abnormalities in prostate cancer. Crit Rev Oncol Hematol 2002; 41: 11-28
• 42 Rui R, Zhou L, He S. Cancer immunotherapies: advances and bottlenecks. Front Immunol 2023; 14: 1212476
• 43 Karwacki J, Kiełbik A, Szlasa W. et al. Boosting the immune response-combining local and immune therapy for prostate cancer treatment. Cells 2022; 11: 2793
• 44 de Bono JS, Guo C, Gurel B. et al. Prostate carcinogenesis: inflammatory storms. Nat Rev Cancer 2020; 20: 455-469
• 45 Lanka SM, Zorko NA, Antonarakis ES. et al. Metastatic castration-resistant prostate cancer, immune checkpoint inhibitors, and beyond. Curr Oncology (Toronto, Ont.) 2023; 30: 4246-4256
• 46 Sharma P, Pachynski RK, Narayan V. et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell 2020; 38: 489-499.e483
• 47 Vodenkova S, Buchler T, Cervena K. et al. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: past, present and future. Pharmacol Therap 2020; 206: 107447
• 48 Wang Y, wie J, Feng L. et al. Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer. Mol Cancer 2023; 22: 81
• 49 Niculae AM, Dobre M, Herlea V. et al. Let-7 microRNAs are possibly associated with perineural invasion in colorectal cancer by targeting IGF axis. Life (Basel, Switzerland) 2022; 12: 1638
• 50 Wen Y, Huang H, Huang B. et al. HSA-miR-34a-5p regulates the SIRT1/TP53 axis in prostate cancer. Am J Transl Res 2022; 14: 4493-4504
• 51 Zhao X, Wang Z, Tang Z. et al. An anoikis-related gene signature for prediction of the prognosis in prostate cancer. Front Oncol 2023; 13: 1169425
• 52 Wu Z, Wu Z, Zeng J. et al. An endoplasmic reticulum stress-related signature featuring ASNS for predicting prognosis and immune landscape in prostate cancer. Aging 2024; 16: 43-65
• 53 Yang B, Jiang Y, Yang J. et al. Characterization of metabolism-associated molecular patterns in prostate cancer. BMC Urol 2023; 23: 104