Cross-System miRNA Profiling Identifies a Clinically Recurrent miRNA Core in Colorectal Cancer

Colorectal cancer (CRC) encompasses biologically diverse cellular phenotypes with distinct microRNA (miRNA) expression patterns. Assessing whether cell-model-derived alterations recur in extracellular vesicles (EVs) and human tumors may help prioritize candidates with broader relevance to CRC. We performed small RNA sequencing of non-malignant HCoEpiC cells, differentiated enterocyte-like Caco-2 cells, less differentiated HCT116 cells, and their corresponding EVs. miRNAs showing concordant dysregulation in both CRC cell lines relative to HCoEpiC, with greater absolute log2 fold changes in HCT116, were prioritized and evaluated in human colorectal tissues and TCGA-COAD/READ. Seven of 29 prioritized cellular miRNAs met the EV selection criteria. Of the 26 candidates measurable in the patient-tissue dataset, eight showed FDR-significant, directionally concordant differences between CRC and healthy colorectal tissues, including five concordantly dysregulated across cells, EVs, and patient tissues. Analysis of 11 matched TCGA tumor–non-tumor pairs reproduced reduced miR-30a-3p, miR-30c-2-3p, and miR-1271-5p and increased miR-140-5p expression. Target-based enrichment and exploratory miRNA-mRNA correlation analyses identified associations with CRC-relevant signaling and MYC-related, cell-cycle, DNA-repair, and metabolic programs. No significant associations with the evaluated clinicopathological features or overall survival were detected. Collectively, these findings identify a reproducible subset of CRC-associated miRNA alterations and highlight reduced miR-30a-3p and miR-30c-2-3p expression as a recurrent family-level pattern warranting mechanistic investigation.