The team first profiled microRNA expression in paired colorectal tumor and adjacent normal tissues using small-RNA sequencing, which showed that miR-183-3p was upregulated in tumor tissue while ESR1 messenger RNA was downregulated. To explore whether circulating miR-183-3p might be causally linked to colorectal cancer, the researchers performed exploratory two-sample Mendelian randomization using expression quantitative trait loci for circulating microRNAs and four FinnGen colorectal cancer-related outcomes. Genetically predicted circulating miR-183-3p showed a nominal association with colon carcinoma in situ, with an inverse-variance-weighted odds ratio of 1.28 (95% confidence interval 1.02–1.60, P = 0.037). However, this association did not survive false discovery rate correction (adjusted P = 0.074) and was not supported by alternative estimators, so the authors treat it as exploratory rather than established causal evidence.

Candidate downstream targets were prioritized through a multi-step pipeline combining target prediction, protein-protein interaction analysis, functional enrichment and an expanded experimentally supported microRNA-target network. ESR1 emerged as a leading candidate, and the expanded network placed the miR-183-3p–ESR1 interaction within a broader many-to-many regulatory architecture, meaning the pair is one node among numerous overlapping microRNA-gene relationships rather than an isolated axis.

Expression evidence came from an independent six-pair tissue cohort and from external validation in The Cancer Genome Atlas colon and rectal adenocarcinoma datasets. In the six tumor samples, miR-183-3p and ESR1 messenger RNA showed a strong but nonsignificant inverse correlation (Spearman ρ = −0.829, P = 0.058), a result limited by the very small sample size. The modest inverse associations were reproduced in the larger TCGA cohorts: TCGA-COAD (n = 443, ρ = −0.219, P < 0.001) and TCGA-READ (n = 160, ρ = −0.279, P < 0.001). These are correlations, not demonstrations of causation, but their consistency across independent datasets strengthens the plausibility of a regulatory relationship.

The most direct evidence came from a dual-luciferase reporter assay in HEK293T cells, in which miR-183-3p directly bound the ESR1 3′ untranslated region and suppressed reporter activity. This confirms a physical binding interaction predicted by the sequence-based analyses. The authors caution, however, that repression of endogenous ESR1 in colorectal cancer cells remains unproven; the assay demonstrates binding to a reporter construct, not physiological silencing of the gene in tumor tissue.

Survival analyses in the TCGA cohorts found no significant association between mature miR-183-3p or ESR1 expression and overall survival, so the molecular relationship does not currently translate into a prognostic marker in the evaluated datasets. The study is framed throughout as hypothesis-generating: it establishes miR-183-3p as a candidate ESR1 3′-UTR-binding microRNA in colorectal cancer and provides converging lines of evidence, but the Mendelian randomization signal is nominal only, the six-pair cohort is small, and functional validation in colorectal cancer cell lines is still lacking.

By laying out both the supporting data and its limits, the work offers a defined starting point for future experiments testing whether miR-183-3p represses endogenous ESR1 in colorectal cancer cells and whether that interaction matters biologically in tumor biology.

Subject of Research: Candidate miR-183-3p regulation of ESR1 in colorectal cancer

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

Article References: Zhao, X., Lai, D., Yao, X., Han, X., Lan, W., Huang, Y., Sun, Y., Li, H., Wang, S., & Zhang, T. (2026). Integrative analysis identifies miR-183-3p as a candidate ESR1 3′-UTR-binding microRNA in colorectal cancer. BMC Cancer. https://doi.org/10.1186/s12885-026-17250-1

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17250-1

Keywords: colorectal cancer, miR-183-3p, ESR1, microRNA, Mendelian randomization, 3′-UTR binding, TCGA, dual-luciferase assay, small-RNA sequencing, BMC Cancer, Integrative, analysis