miRNA Signatures in Endometrial Cancer: Implications for Oncogenesis and Polymerase Epsilon (POLE) Mutation Status

TL;DR

This study identifies miRNA patterns in endometrial cancer, showing significant differences in tumors with POLE mutations compared to others, suggesting miRNAs could help classify and treat the disease.

Contribution

The study reveals a unique miRNA down-regulation signature in POLE-mutated endometrial tumors, offering new insights into cancer classification and biomarker development.

Findings

Endometrial cancer tissues showed 50 significantly dysregulated miRNAs compared to healthy controls, including oncogenic up-regulation and tumor-suppressive down-regulation.

POLE-mutated tumors exhibited a distinct miRNA signature with 19 significantly down-regulated miRNAs, such as let-7f-5p and hsa-miR-200b-3p.

Findings were validated using TCGA-UCEC data, confirming consistent miRNA dysregulation across platforms.

Abstract

MicroRNAs (miRNAs) are key regulators of gene expression with critical roles in oncogenic signaling. Endometrial cancer (EC) has been redefined with the identification of POLE-ultramutated tumors which, despite their hypermutated phenotype, show more favorable prognosis. We profiled miRNA expression in tumor tissues from forty (40) EC patients and twenty (20) healthy controls using qPCR panels. POLE exonuclease domain mutations (P286R, V411L) were genotyped, and subgroup analyses were conducted between POLE-mutated (n = 7) and POLE-wild-type (n = 33) tumors. Bioinformatic analyses included validated miRNA–mRNA interactions, target enrichment, and Gene Ontology (GO) pathway mapping. Comparison of EC versus healthy endometrium revealed 50 significantly dysregulated (∣log2 (FoldReg)∣ > 1 and BH FDR < 0.05) miRNAs, including up-regulation of the oncogenic hsa-miR-181a-5p, hsa-miR-23a-3p, hsa-miR-200c-3p, and down-regulation of tumor-suppressive let-7 family members. Target enrichment implicated canonical oncogenic regulators such as MYC, TP53, and VEGFA. POLE-mutated tumor analysis demonstrated a miRNA signature, with 19 miRNAs significantly down-regulated, including let-7f-5p and hsa-miR-200b-3p. Findings for the EC versus healthy endometrium comparison were validated against TCGA-UCEC sequencing data which confirmed concordant dysregulation of key miRNAs across platforms. Our findings reveal that EC is characterized by widespread miRNA deregulation, with a unique global down-regulation signature in POLE-mutated tumors. These results highlight the potential of miRNAs as complementary biomarkers for classification and potential targets in EC.

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