Integrative analysis identifies miR-183-3p as a candidate ESR1 3′-UTR-binding microRNA in colorectal cancer

MicroRNA-183-3p (miR-183-3p) is dysregulated in colorectal cancer (CRC), but its downstream targets and biological relevance remain incompletely defined. We investigated the potential relationship between miR-183-3p and estrogen receptor 1 ( ESR1 ) using an integrative, hypothesis-generating framework. Differentially expressed miRNAs were identified by small-RNA sequencing of paired CRC and adjacent tissues. Exploratory two-sample Mendelian randomization (MR) used circulating miRNA expression quantitative trait loci and four FinnGen CRC-related outcomes. Candidate targets were prioritized by target prediction, protein-protein interaction analysis, functional enrichment, and an expanded experimentally supported miRNA-target network. miR-183-3p and ESR1 expression were evaluated in an independent six-pair tissue cohort, with external validation in TCGA-COAD and TCGA-READ. Direct binding to the ESR1 3′-UTR was assessed by dual-luciferase assay in HEK293T cells, and overall survival was explored in TCGA cohorts. miR-183-3p was upregulated and ESR1 mRNA was downregulated in CRC tissues. MR showed a nominal association between genetically predicted circulating miR-183-3p and colon carcinoma in situ (IVW OR = 1.28, 95% CI 1.02–1.60, P = 0.037), but the association did not survive FDR correction (adjusted P = 0.074) or receive support from alternative estimators. ESR1 was prioritized as a candidate target, and expanded network analysis placed the miR-183-3p– ESR1 interaction within a broader many-to-many regulatory architecture. In six tumor samples, miR-183-3p and ESR1 mRNA showed a nonsignificant inverse association (Spearman ρ = −0.829, P = 0.058). Modest inverse associations were reproduced in TCGA-COAD ( n = 443, ρ = −0.219, P < 0.001) and TCGA-READ ( n = 160, ρ = −0.279, P < 0.001). miR-183-3p directly bound the ESR1 3′-UTR and suppressed reporter activity in HEK293T cells. Mature miR-183-3p and ESR1 were not significantly associated with overall survival in the evaluated TCGA cohorts. The findings support miR-183-3p as a candidate ESR1 3′-UTR-binding miRNA in CRC. However, the MR evidence remains exploratory, and functional repression of endogenous ESR1 in CRC cells remains unproven.