Identification of One-carbon metabolism-related gene signature and Analysis of the role of m6A and miRNAs/circRNAs for colon adenocarcinoma

Abstract

Background: To study one-carbon metabolism-related genes and their association with Colon adenocarcinoma (COAD) prognosis, immune cell infiltration, and search for new therapeutic targets and drugs. Methods: The univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression for COAD prognosis from The Cancer Genome Atlas (TCGA), and the prognostic efficacy of the one carbon unit and amino acid -related gene signature was assessed using Kaplan–Meier (KM) survival and receiver operating characteristic (ROC) curve analyses. The co-expression of one-carbon metabolism -related genes with miRNAs or circRNAs and M6A-related genes in COAD was analyzed. Using CIBERSORT, and single-sample GSEA (ssGSEA) algorithms, the quantities and types of tumor-infiltrating immune cells were assessed. Potential small-molecule agents were identified using the GDSC database and validated by molecular docking. To verify key core gene expression levels, quantitative real-time polymerase chain reaction (qRT–PCR) assays were conducted. Results: We identified three one-carbon metabolism -related genes (AHCY, BHMT, SLC38A2) for the prognostic signature of overall survival (OS) for COAD. The binding information between metabolism-related genes, target miRNAs and circRNAs indicated that miR-140-5p and miR-195-5p/ hsa_circ_0071989had a good prediction. The chemotherapeutic agent sensitivity of patients categorized by risk score varied significantly. AHCY and BHMT, SLC38A2 mRNA expression was increased in HCT116 cells, whereas miRNA (miR-140-5p and miR-195-5p) expression was decreased in HCT116 cells. Conclusion:In summary, we identified and developed a one-carbon metabolism -related gene signature with significant prognostic value of COAD, and AHCY, BHMT, SLC38A2 were positively regulated by the m6A genes in COAD samples. The combination TGX221 with cyclopamin significantly decreased AHCY, BHMT and SLC38A2 via upregulating miR-140-5p and miR-195-5p in HCT116 cells, which benefits COAD patients by informing more precise and effective treatment decisions.