Comprehensive analysis of miRNA-mRNA regulatory pairs associated with colorectal cancer and the role in tumor immunity.

Background: MicroRNA (miRNA) which can act as post-transcriptional regulators of mRNAs via base-pairing with complementary sequences within mRNAs is involved in processes of the complex interaction between immune system and tumors. In this research, we elucidated the profiles of miRNAs and target mRNAs expression and their associations with the phenotypic hallmarks of colorectal cancers (CRC) by integrating transcriptomic, immunophenotype, methylation, mutation and survival data.

Results: We conducted the analysis of differential miRNA/mRNA expression profile by GEO, TCGA and GTEx databases and the correlation between miRNA and targeted mRNA by miRTarBase and TarBase. Then we detected using qRT-PCR and validated the diagnostic value of miRNA-mRNA regulator pairs by the ROC, calibration curve and DCA. Phenotypic hallmarks of regulatory pairs including tumor-infiltrating lymphocytes, tumor microenvironment, tumor mutation burden, global methylation and gene mutation were also described. The expression levels of miRNAs and target mRNAs were detected in 80 paired colon tissue samples. Ultimately, we picked up two pivotal regulatory pairs (miR-139-5p/ STC1 and miR-20a-5p/ FGL2) and verified the diagnostic value of the complex model which is the combination of 4 signatures above-mentioned in 3 testing GEO datasets and an external validation cohort.

Conclusions: We found that 2 miRNAs by targeting 2 metastasis-related mRNAs were correlated with tumor-infiltrating macrophages, HRAS, and BRAF gene mutation status. Our results established the diagnostic model containing 2 miRNAs and their respective targeted mRNAs to distinguish CRCs and normal controls and displayed their complex roles in CRC pathogenesis especially tumor immunity.