Evaluation of genetic variation in tumor suppressor miRNA encoding and their target genes in breast cancer; focus on miRNA interaction and expression analysis

TL;DR

This study explores how genetic variations in tumor suppressor miRNAs and their target genes, specifically KRAS, affect breast cancer risk and survival outcomes.

Contribution

The study identifies specific KRAS 3′UTR variants that disrupt miRNA binding and links miRNA expression levels to better survival in breast cancer patients.

Findings

Variants rs712 and rs9266 in KRAS 3′UTR disrupt miRNA binding and increase KRAS expression.

Higher hsa-let-7c and hsa-miR-181c expression correlates with better survival in breast cancer patients.

KRAS is identified as a potential predictive biomarker for chemotherapy response.

Abstract

Genetic variations in tumor suppressor miRNAs and the 3′UTR of their target genes influence tumor biology and breast cancer (BC) risk.

This study investigated genetic variations in tumor suppressor miRNAs (hsa-let-7c, hsa-miR-34a, hsa-miR-145a) and their target genes (KRAS, IGFBP6, IGF1R), and their functional significance in BC patients.

The miRNA encoding regions and 3′UTRs of the selected target genes were sequenced in 208 BC patients. Functional analyses were performed using luciferase assay, RT-PCR, IHC, and Western blotting. RNAfold, TNM plot, Kaplan-Meier Plotter, and ROC Plotter were used for structural predictions, survival, and therapy response analysis.

Two variants, rs712 and rs9266, were found in the 3′UTR of KRAS. Luciferase assay confirmed that rs9266 disrupts the binding of hsa-let-7c and hsa-miR-181c, leading to increased KRAS expression. KRAS expression was highest in heterozygous, followed by homozygous mutant, and lowest in wild-type genotypes. Higher hsa-let-7c and hsa-miR-181c expression correlated with better survival. ROC analysis identified KRAS as a potential predictive biomarker for chemotherapy response.

Variants rs712 and rs9266 in the KRAS 3′UTR impair miRNA binding, enhancing KRAS expression and tumorigenesis, while elevated hsa-let-7c and hsa-miR-181c levels predict favourable survival outcomes in BC patients.

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