MiR-182-Mediated Downregulation of BRCA1 and Upregulation of HMGA2 in High-Grade Serous Ovarian Cancer
Introduction. Ovarian cancer is the leading cause of mortality from gynecological malignancy in the US due to a lack of screening and a lack of early detection. The most common type is high-grade serous ovarian cancer (HGSOC),1 originating from serous tubal intraepithelial carcinomas of the fimbriated end of the fallopian tube2. Numerous miRNAs are expressed in the ovary that are involved in ovarian processes and dysregulation of these miRNAs play important roles in ovarian diseases3. Studies have shown that local oxidative stress and inflammation that occurs during each menstrual cycle increased the production of miR-1824. MiR-182 overexpression in fallopian tube epithelial, ovarian surface epithelial, and ovarian cancer cell lines showed significantly reduced BRCA1 (tumor suppressor gene) and enhanced HMGA2 (transcription factor) expression, affecting double-stranded break repairs and enhancing tumor metastasis5. These findings could suggest a potential treatment for high-grade serous ovarian cancer6. Methods. Female athymic 8-week old mice were used. SKOV3 tumor cells were implanted in the left ovarian intrabursal space of 40 mice to mimic the microenvironment of human ovarian cancer and OVCAR3 tumor cells were injected into the peritoneum of another 14 mice. Both cancer cell lines had a stable miR-182 overexpression and were transfected with luciferase to monitor tumor growth via in vivo bioluminescence imaging. The mice in the test group were treated with anti-miR-182 injections twice weekly. All of the mice were maintained in laminar flow rooms, with consistent temperature and humidity, and were given free access to water and a normal diet throughout the 8 weeks. The mice were sacrificed after 8 weeks of anti-miR-182 treatment and all of the peritoneal organs, heart, and lungs of the mice with SKOV3 cancer cell lines were examined for cancer metastases6. Results. After 8 weeks of treatment, the tumors of the mice with SKOV3 and OVCAR3 xenografts were smaller compared to their control groups. Thirty-one metastases were found in the control group compared to 6 metastases in the treated mice. Real-time PCR confirmed that all of the treated tumors expressed very low to non-detectable levels of miR-1826. Conclusions. Studies support that miR-182 overexpression leads to dysregulation of BRCA1 and HMGA2, which plays a part in early tumorigenesis of HGSOC because BRCA1 repairs double-stranded breaks and HMGA2 promotes ovarian cancer invasion5. The use of an anti-miR-182 treatment could potentially be useful in reducing cancer metastases in HGSOC6 and should be further investigated.
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