The development of a novel signature based on the m6A RNA methylation regulator-related ceRNA network to predict prognosis and therapy response in sarcomas

Abstract

Background: N6 methyladenosine (m6A)-related noncoding RNAs (including lncRNAs and miRNAs) are closely related to the development of cancer. However, the gene signature and prognostic value of m6A regulators and m6A-associated RNAs in regulating sarcoma (SARC) development and progression remain largely unexplored. Therefore, further research is required.Methods: We obtained expression data for RNA sequencing (RNA-seq) and miRNAs of SARC from The Cancer Genome Atlas (TCGA) datasets. Correlation analysis and two target gene prediction databases (miRTarBase and LncBase v.2) were used to deduce m6A-related miRNAs and lncRNAs, and Cytoscape software was used to construct ceRNA-regulating networks. Based on univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, an m6A-associated RNA risk signature (m6Ascore) model was established. Prognostic differences between subgroups were explored using Kaplan–Meier (KM) analysis. Risk score-related biological phenotypes were analyzed in terms of functional enrichment, tumor immune signature, and tumor mutation signature. Finally, potential immunotherapy features and drug sensitivity predictions for this model were also discussed.Results: A total of 16 miRNAs, 104 lncRNAs, and 11 mRNAs were incorporated into the ceRNA network. The risk score was obtained based on RP11-283I3.6, hsa-miR-455-3p, and CBLL1. Patients were divided into two risk groups using the risk score, with patients in the low-risk group having longer overall survival (OS) than those in the high-risk group. The receiver operating characteristic (ROC) curves indicated that risk characteristic performed well in predicting the prognosis of patients with SARC. In addition, lower m6Ascore was also positively correlated with the abundance of immune cells such as monocytes and mast cells activated, and several immune checkpoint genes were highly expressed in the low-m6Ascore group. According to our analysis, lower m6Ascore may lead to better immunotherapy response and OS outcomes. The risk signature was significantly associated with the chemosensitivity of SARC. Finally, a nomogram was constructed to predict the OS in patients with SARC. The concordance index (C-index) for the nomogram was 0.744 (95% CI: 0.707–0.784). The decision curve analysis (DCA), calibration plot, and ROC curve all showed that this nomogram had good predictive performance.Conclusion: This m6Ascore risk model based on m6A RNA methylation regulator-related RNAs may be promising for clinical prediction of prognosis and might contain potential biomarkers for treatment response prediction for SARC patients.

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

“…m6A modification is reversibly modulated through the installation of methyl transferases (writers), the removal of a methyl group by demethylases (erasers), and the recognition of m6A binding proteins (readers) [ 22 , 23 ]. m6A writers and associated proteins (m6A writer complex) include Vir-like m6A methyl transferase-associated protein (VIRMA) [ 24 ], methyl transferase-like protein 3 (METTL3) [ 25 ], METTL4 [ 26 ], MTTL5 [ 27 ], METTL14 [ 28 ], METTL 16 [ 29 ], Wilms’ tumor 1 associated protein (WTAP) [ 30 , 31 ], RNA-binding motif protein 15/15B (RBM15/15B) [ 32 ], casitas B-lineage lymphoma-transforming sequence-like protein 1 (CBLL1) [ 33 ], zinc finger CCCH-type containing 13 (ZC3H13), and zinc finger CCHC-type containing 4 (ZCCHC4) [ 5 , 34 , 35 , 36 , 37 , 38 ]. RBM15/15B, VIRMA, CBLL1, ZCCHC4, and ZC3H13 act as associated proteins of m6A writers.…”

Exploring miRNA–target gene pair detection in disease with coRmiT

“…In addition, there are studies that filter the detected mTPs using databases of experimentally validated mTPs [ 22 ]. Such databases include miRTarBase [ 23 ], Tarbase [ 24 ] and miRecords [ 25 ].…”