Reduced Levels of miR-145-3p Drive Cell Cycle Progression in Advanced High-Grade Serous Ovarian Cancer

Area of Science:

• Gynecologic Oncology
• Epigenetics
• Molecular Biology

Background:

• High-grade serous ovarian cancer (HGSOC) is a lethal gynecologic malignancy with poor prognosis and limited therapeutic options.
• Epigenetic dysregulation, including microRNAs (miRNAs) and DNA methylation, is implicated in HGSOC progression but requires further elucidation.
• Understanding these epigenetic mechanisms is crucial for developing novel treatment strategies.

Purpose of the Study:

• To identify dysregulated miRNAs in HGSOC using high-throughput analysis.
• To investigate the epigenetic regulation, specifically DNA methylation, of identified miRNAs.
• To explore the functional role of a key miRNA, miR-145-3p, in HGSOC cell behavior.

Main Methods:

• Comprehensive high-throughput screening to identify differentially expressed miRNAs in HGSOC tissues.
• Quantitative reverse transcription PCR (RT-qPCR) for miRNA validation in patient samples and cell lines.
• DNA methylation analysis to assess epigenetic control of miRNA expression.
• Functional assays (cell migration, cell cycle analysis) to determine the impact of miR-145-3p modulation.

Main Results:

• Twenty differentially expressed miRNAs were identified in HGSOC, with 11 validated by RT-qPCR.
• miR-145-3p was consistently downregulated in advanced-stage HGSOC and post-neoadjuvant therapy, distinguishing tumor from control tissues.
• DNA methylation was confirmed as the regulatory mechanism controlling *MIR145* expression.
• Overexpression of miR-145-3p suppressed HGSOC cell migration and induced G0/G1 cell cycle arrest via the cyclin D1-CDK4/6 pathway.

Conclusions:

• Downregulation of miR-145-3p, driven by DNA methylation, promotes cell proliferation and migration in HGSOC.
• Restoration of miR-145-3p represents a potential therapeutic strategy targeting G1/S phase regulation in HGSOC treatment.
• This study highlights the critical role of epigenetic modifications in HGSOC pathogenesis and identifies a promising biomarker and therapeutic target.