A dynamic miRNA-mRNA network serves as a crosstalk between abnormal cell cycle and immunosuppressive microenvironment in the colorectal adenoma-carcinoma sequence

Abstract

Abstract Background Colorectal tumorigenesis is well accepted with the colorectal adenoma-carcinoma sequence (ACS). MicroRNAs (miRNAs) have been considered as effective biomarkers for colorectal cancer (CRC) or adenoma detection. However, it is unclear how miRNAs initiate CRC. Methods In our study, we collected multiple public datasets with miRNA (GSE41655 and GSE115513) or mRNA (GSE41657 and GSE37364) consisting of normal tissue, benign adenoma, and malignant tumor samples. STEM analysis was performed to investigate dynamic deregulated miRNAs and mRNAs along the colorectal ACS. The miRNA-mRNA regulatory network was constructed on two miRNA-target prediction databases (tarBase and miRTarBase). WGCNA, KEGG pathway analysis, and GSEA were used to explore the potential molecular biological function. The lineage trajectory in the colorectal ACS was identified via monocle analysis based on a single-cell RNA sequencing data (GSE161277). ESTIMATE analysis and Immune cell infiltration analysis were used to examine the contribution of different cell types in the microenvironment of ACS. Drug sensitivity analysis of common targeting drugs was performed on OncoPredict R package and immune checkpoint blockade (ICB) response was predicted by TIDE analysis. Results A total of 4 dynamic down-regulated miRNAs and 278 dynamic up-regulated mRNAs were investigated. We then conducted a 4 down-regulated miRNA-25 up-regulated mRNA regulatory network, which well distinguished among normal, adenoma, CRC samples. Mechanistically, the signature of 25 target genes (Sig-25Targets) was positively associated with cell cycle-related pathways, while negatively correlated with immune-related pathways. Furthermore, the Sig-25Targets showed similar increasing score as the “cell cycle”, “G2/M checkpoint”, and “DNA repair” along the ACS via epithelial cell lineage transition. On the other hand, we found a negatively association between this signature and immune score, especial the B cell in the adenoma and CRC samples. Clinically, drug sensitivity analysis showed that Sig-25Targets was sensitive with cell cycle targeting drugs, but had a worse overall survival with datasets using ICB treatment. Conclusions Overall, our results revealed that the 4 down-regulated miRNA-25 up-regulated mRNA regulatory network may participate in the colorectal ACS through the abnormal activation of cell cycle signaling, but as an immunosuppressor. We also provide potential treatment guidance for CRC patients who significantly express these genes.