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miR-449, identified through antiandrogen exposure, mitigates functional biomarkers associated with ovarian cancer
Xia Wang1,2, Ho-Hyung Woo3,4, Michelle Wei2
1College of Animal Science and Technology, Northwest A&F University, Shaanxi, China.
Abstract:
The involvement of the androgen receptor (AR) pathway in developing epithelial ovarian cancer is increasingly acknowledged. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. This study was initiated by investigating the impact of flutamide on miRNA expression in women at high risk (HR) for ovarian cancer. Ovarian and tubal tissues, free from ovarian, tubal, peritoneal cancers, and serous tubal intraepithelial carcinoma (STIC), were collected from untreated and flutamide-treated HR women as well as low-risk (LR) women controls. We performed miRNA sequencing on these 3 sample cohorts and observed that flutamide normalized miRNA levels in HR tissues, notably upregulating the miR-449 family to levels seen in LR tissues. In subsequent tests in primary ovarian epithelial cells and ovarian cancer cell lines (SKOV3 and Hey), flutamide also increased miR-449a and miR-449b-5p levels. Introducing mimics of these miRNAs reduced the mRNA and protein levels of AR and colony-stimulating factor 1 receptor (CSF1R, also known as c-fms), both of which are known contributors to ovarian cancer progression, with emerging evidence also supporting their roles in ovarian cancer initiation. Ovarian cancer cell migration was inhibited upon introducing miR-449a and miR-449b-5p mimics. Together, our study suggests a novel dual-inhibitory mechanism of flutamide on the AR pathway (AR expression suppression in addition to direct androgen antagonism) and supports its chemopreventive potential in ovarian cancer, especially for HR patients with low miR-449 expression.
Insights
Flutamide, an anti-androgen drug, normalizes microRNA levels in women at high risk for ovarian cancer. It upregulates miR-449, suppressing androgen receptor and CSF1R, suggesting potential ovarian cancer chemoprevention.
Area of Science:
- Molecular Oncology
- Endocrinology
- Genomics
Background:
- The androgen receptor (AR) pathway is implicated in epithelial ovarian cancer development.
- The preventive mechanisms and efficacy of anti-androgen agents like flutamide in ovarian cancer are not well understood.
Purpose of the Study:
- To investigate the impact of flutamide on miRNA expression in high-risk (HR) women for ovarian cancer.
- To elucidate the molecular mechanisms underlying flutamide's potential chemopreventive effects against ovarian cancer.
Main Methods:
- miRNA sequencing was performed on ovarian and tubal tissues from untreated HR women, flutamide-treated HR women, and low-risk (LR) controls.
- Experiments in primary ovarian epithelial cells and ovarian cancer cell lines (SKOV3, Hey) were conducted using miRNA mimics.
- Analysis included measuring mRNA and protein levels of AR and CSF1R, and assessing ovarian cancer cell migration.
Main Results:
- Flutamide treatment normalized miRNA levels in HR tissues, significantly upregulating the miR-449 family to levels observed in LR tissues.
- Flutamide increased miR-449a and miR-449b-5p levels in ovarian cells; introducing these miRNA mimics reduced AR and CSF1R expression.
- Overexpression of miR-449a and miR-449b-5p inhibited ovarian cancer cell migration.
Conclusions:
- Flutamide exhibits a novel dual-inhibitory mechanism against the AR pathway by suppressing AR expression and direct androgen antagonism.
- The study supports flutamide's potential as a chemopreventive agent for ovarian cancer, particularly in high-risk individuals with low miR-449 expression.
