MicroRNA miR-183-3p emerges as candidate regulator of ESR1 in colorectal cancer

An integrative genomic study has identified microRNA-183-3p as a candidate microRNA that binds the 3′ untranslated region of the estrogen receptor 1 gene (ESR1) in colorectal cancer. The research, published open access in BMC Cancer, combined small-RNA sequencing, Mendelian randomization, network analysis, independent tissue cohorts and a luciferase assay to build a hypothesis-generating case for a miR-183-3p–ESR1 regulatory relationship, while explicitly stopping short of proving functional repression in colorectal cancer cells.

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