TMPO-AS1-hsa-let-7b-5p-EZH2-RNA network predicts poor survival in basal-like breast cancer patients
Abstract
Background: The study explores the role of non-coding ribonucleic acids (RNAs) and higher enhancer of zeste homolog 2 (EZH2) gene in breast cancer progression, examining how micro RNA (miRNA) and long noncoding RNA (lncRNA) control EZH2, potentially influencing oncogene growth and treatment failure.
Materials and methods: The databases used in the study included Cyclebase 3.0 and CellTracer to determine EZH2’s role in cell cycle, Oncomine, OncoMX and The University of Alabama At Birmingham Cancer Data Analysis Portal (UALCAN) for Pan-cancer analysis, The Cancer Genomic Atlas Portal (TCGA Portal), Gene Expression Profiling Interactive Analysis (GEPIA2), OncoDB, CR2Cancer, Encyclopaedia of RNA Interactomes (ENCORI), and The Cancer Genome Altas Analyzer (TCGAnalyzeR v1.0) for differential expression analysis, CR2Cancer, OncoDB, MethMarkerDB, and Wanderer databases for epigenetic alteration analysis, Kaplan-Meier Plotter for survival analysis, Breast Cancer Gene Expression Miner (bc-GenExMiner v5.0) for hormone receptor analysis, Tumor-Immune System Interaction Database (TISIDB), Cancer Single Cell State Atlas (CancerSEA), TNMplot, DriverDBv4, and ENCORI for biological processes, cell cycle checkpoints and metastasis analysis, Enrichr, Tumor Immune Estimation Resource (TIMER 2.0), Gepia2 for transcription factor analysis, miRNet, Transcriptome Alterations in Cancer Omnibus (TACCO), and CancerMIRome for miRNA analysis, Enrichr, UALCAN, and ENCORI for lncRNA analysis.
Results: The EZH2 gene is overexpressed in breast cancer (BRCA) tumors, metastatic tissues, and circulating tumor cells, potentially leading to cancer progression. Patients with high EZH2 expression have shorter overall survival (OS), distant metastasis-free survival (DMFS), and relapse-free survival (RFS) compared to those with low expression. Estrogen receptot (ER)-negative BRCA tumors and PR-negative tumors have EZH2 gene and eucariotic transcription factor (E2F2) levels. The EZH2/E2F2 axis may assist ER/PR-negative BRCA by sponging homosapiens microRNA family (hsa-let-7b-5p) through lncRNA-thymopoietin antisense transcript 1 (TMPO-AS1). Overexpression of the EZH2 protein is associated with BRCA metastasis.
Conclusion: EZH2 overexpression in basal-like BRCA is mediated by a competing endogenous RNA (ceRNA) network and regulating their expression levels may facilitate better survival outcomes.
Keywords: breast cancerceRNA networkEZH2Kaplan-Meier Plotterprognosis
References
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209–249.
- Yang R, Wu Y, Qi Y, et al. A nomogram for predicting breast cancer specific survival in elderly patients with breast cancer: a SEER population-based analysis. BMC Geriatr. 2023; 23(1): 594.
- Castellarnau-Visús M, Soveral I, Regueiro Espín P, et al. Prognostic factors in Luminal B-like HER2-negative breast cancer tumors. Surg Oncol. 2023; 49: 101968.
- Campbell HE, Gray AM, Harris AL, et al. Estimation and external validation of a new prognostic model for predicting recurrence-free survival for early breast cancer patients in the UK. Br J Cancer. 2010; 103(6): 776–786.
- Abdul Wahab MR, Palaniyandi T, Viswanathan S, et al. Biomarker-specific biosensors revolutionise breast cancer diagnosis. Clin Chim Acta. 2024; 555: 117792.
- Liu Z, Li J, Zhao F, et al. Long-term survival after neoadjuvant therapy for triple-negative breast cancer under different treatment regimens: a systematic review and network meta-analysis. BMC Cancer. 2024; 24(1): 440.
- Dailah HG, Hommdi AA, Koriri MD, et al. Potential role of immunotherapy and targeted therapy in the treatment of cancer: A contemporary nursing practice. Heliyon. 2024; 10(2): e24559.
- Rakha EA, Pareja FG. New Advances in Molecular Breast Cancer Pathology. Semin Cancer Biol. 2021; 72: 102–113.
- Varnier R, Sajous C, de Talhouet S, et al. Using Breast Cancer Gene Expression Signatures in Clinical Practice: Unsolved Issues, Ongoing Trials and Future Perspectives. Cancers (Basel). 2021; 13(19).
- Chen Y, Zhu H, Luo Yi, et al. EZH2: The roles in targeted therapy and mechanisms of resistance in breast cancer. Biomed Pharmacother. 2024; 175: 116624.
- Yu F, Li L, Zhang M, et al. Phosphorylation of EZH2 differs HER2-positive breast cancer invasiveness in a site-specific manner. BMC Cancer. 2023; 23(1): 948.
- Yang Y, Fan H, Liu H, et al. NOP2 facilitates EZH2-mediated epithelial-mesenchymal transition by enhancing EZH2 mRNA stability via m5C methylation in lung cancer progression. Cell Death Dis. 2024; 15(7): 506.
- Li F, Wang P, Ye J, et al. Serum EZH2 is a novel biomarker for bladder cancer diagnosis and prognosis. Front Oncol. 2024; 14: 1303918.
- Freitag T, Kaps P, Ramtke J, et al. Combined inhibition of EZH2 and CDK4/6 perturbs endoplasmic reticulum-mitochondrial homeostasis and increases antitumor activity against glioblastoma. NPJ Precis Oncol. 2024; 8(1): 156.
- Ozgun G, Yaras T, Akman B, et al. Retinoids and EZH2 inhibitors cooperate to orchestrate anti-oncogenic effects on bladder cancer cells. Cancer Gene Ther. 2024; 31(4): 537–551.
- Zhang Q, Shi Y, Liu S, et al. EZH2/G9a interact to mediate drug resistance in non-small-cell lung cancer by regulating the SMAD4/ERK/c-Myc signaling axis. Cell Rep. 2024; 43(2): 113714.
- Santos A, Wernersson R, Jensen LJ. Cyclebase 3.0: a multi-organism database on cell-cycle regulation and phenotypes. Nucleic Acids Res. 2015; 43(Database issue): D1140–D1144.
- Guo Q, Wang P, Liu Q, et al. CellTracer: a comprehensive database to dissect the causative multilevel interplay contributing to cell development trajectories. Nucleic Acids Res. 2023; 51(D1): D861–D869.
- Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004; 6(1): 1–6.
- Dingerdissen HM, Bastian F, Vijay-Shanker K, et al. OncoMX: A Knowledgebase for Exploring Cancer Biomarkers in the Context of Related Cancer and Healthy Data. JCO Clin Cancer Inform. 2020; 4: 210–220.
- Chandrashekar DS, Karthikeyan SK, Korla PK, et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022; 25: 18–27.
- Xu S, Feng Y, Zhao S. Proteins with Evolutionarily Hypervariable Domains are Associated with Immune Response and Better Survival of Basal-like Breast Cancer Patients. Comput Struct Biotechnol J. 2019; 17: 430–440.
- Tang Z, Kang B, Li C, et al. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019; 47(W1): W556–W560.
- Tang G, Cho M, Wang X. OncoDB: an interactive online database for analysis of gene expression and viral infection in cancer. Nucleic Acids Res. 2022; 50(D1): D1334–D1339.
- Ru B, Sun J, Tong Y, et al. CR2Cancer: a database for chromatin regulators in human cancer. Nucleic Acids Res. 2018; 46(D1): D918–D924.
- Li JH, Liu S, Zhou H, et al. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014; 42(Database issue): D92–D97.
- Zengin T, Masud B, Önal-Süzek T. TCGAnalyzeR: a web application for integrative visualization of molecular and clinical data of cancer patients for cohort and associated gene discovery. Cancers (Basel). 2024; 16(2): 345–10.3390/cancers16020345.
- Zhu Z, Zhou Q, Sun Y, et al. MethMarkerDB: a comprehensive cancer DNA methylation biomarker database. Nucleic Acids Res. 2024; 52(D1): D1380–D1392.
- Díez-Villanueva A, Mallona I, Peinado MA. Wanderer, an interactive viewer to explore DNA methylation and gene expression data in human cancer. Epigenetics Chromatin. 2015; 8: 22.
- Jézéquel P, Gouraud W, Ben Azzouz F, et al. bc-GenExMiner 4.5: new mining module computes breast cancer differential gene expression analyses. Database (Oxford). 2021; 2021.
- Ru B, Wong CN, Tong Y, et al. TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics. 2019; 35(20): 4200–4202.
- Yuan H, Yan M, Zhang G, et al. CancerSEA: a cancer single-cell state atlas. Nucleic Acids Res. 2019; 47(D1): D900–D908.
- Bartha Á, Győrffy B. TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues. Int J Mol Sci. 2021; 22(5).
- Liu CH, Lai YL, Shen PC, et al. DriverDBv4: a multi-omics integration database for cancer driver gene research. Nucleic Acids Res. 2024; 52(D1): D1246–D1252.
- Győrffy B. Discovery and ranking of the most robust prognostic biomarkers in serous ovarian cancer. Geroscience. 2023; 45(3): 1889–1898.
- Xie Z, Bailey A, Kuleshov MV, et al. Gene Set Knowledge Discovery with Enrichr. Curr Protoc. 2021; 1(3): e90.
- Li T, Fan J, Wang B, et al. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21): e108–e110.
- Chang Le, Xia J. MicroRNA Regulatory Network Analysis Using miRNet 2.0. Methods Mol Biol. 2023; 2594: 185–204.
- Chou PH, Liao WC, Tsai KW, et al. TACCO, a Database Connecting Transcriptome Alterations, Pathway Alterations and Clinical Outcomes in Cancers. Sci Rep. 2019; 9(1): 3877.
- Li R, Qu H, Wang S, et al. CancerMIRNome: an interactive analysis and visualization database for miRNome profiles of human cancer. Nucleic Acids Res. 2022; 50(D1): D1139–D1146.
- Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020; 48(W1): W509–W514.
- Samaržija I, Tomljanović M, Novak Kujundžić R, et al. EZH2 Inhibition and Cisplatin as a Combination Anticancer Therapy: An Overview of Preclinical Studies. Cancers (Basel). 2022; 14(19).
- Mao Q, Wu P, Li H, et al. CRISPR/Cas9‑mediated EZH2 knockout suppresses the proliferation and migration of triple‑negative breast cancer cells. Oncol Lett. 2023; 26(2): 343.
- Verma A, Singh A, Singh MP, et al. EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis. Nat Commun. 2022; 13(1): 7344.
- Wu SC, Zhang Yi. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. J Biol Chem. 2011; 286(32): 28511–28519.
- Chen S, Bohrer LR, Rai AN, et al. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol. 2010; 12(11): 1108–1114.
- Xia H, Zhang W, Li Y, et al. EZH2 silencing with RNA interference induces G2/M arrest in human lung cancer cells in vitro. Biomed Res Int. 2014; 2014: 348728.