The PAX8-CCDC80-B7H3 pathway is a driver of ovarian cancer cell migration
2Division of Oncology, Clinical Research Institute at Rambam, Rambam Medical Center, Israel
High grade serous ovarian cancer (HGSC), the most common subtype of ovarian cancer, often arises from transformation of fallopian tube cells. PAX8 is a master regulator of transcription in fallopian tube development and in HGSC, and its expression is maintained during transformation to HGSC. PAX8 plays an essential oncogenic role in HGSC, but little is known about PAX8 target genes in this disease. Therefore, our aim was to identify novel mediators of the oncogenic role of PAX8 in HGSC and to discover its molecular mechanism. To address this, we performed bioinformatic analysis for genome-wide datasets of PAX8 co-regulated genes and found several potential PAX8 target genes. After experimental validations, CCDC80 was selected for further study based on its robust negative regulation by PAX8 in multiple HGSC cell lines. Our results show that CCDC80 inhibits cell migration and colony formation in HGSC, and that the negative regulation of CCDC80 mediates the pro-migratory role of PAX8. To explore the molecular mechanism of CCDC80 in HGSC, we over-expressed CCDC80 and used Mass-Spectrometry to test for CCDC80 regulated proteins. Our analysis revealed B7-H3 as one of the most significantly down regulated proteins upon CCDC80 overexpression. To test whether B7H3 can mediate the role of CCDC80 in HGSC, B7-H3 will be silenced and tested for the ability of HGSC cells to migrate and form colonies. Our results suggest that CCDC80 is a novel PAX8 regulated tumor suppressor gene in HGSC, and that this negative regulation can drive transformation potentially through B7-H3.