<scp>CCDC80</scp> suppresses high‐grade serous ovarian cancer migration via negative regulation of <scp>B7</scp> ‐ <scp>H3</scp>

Paired box protein Pax-8 (PAX8) is a critical lineage marker and master regulator of transcription in high-grade serous ovarian carcinoma (HGSC)-the most common subtype of epithelial ovarian cancer-driving cell proliferation and migration and resisting apoptosis. This study aimed to elucidate the mechanism of action of PAX8 in this disease. By performing an unbiased analysis of PAX8-regulated genes, we discovered two PAX8-regulated genes-coiled-coil domain-containing protein 80 (CCDC80) and cluster of differentiation 276 (CD276) antigen (also known as B7-H3)-that mediate PAX8 activity and play key cancer cell autonomous roles in this disease. Our findings indicate that PAX8 negatively regulates CCDC80, a novel cell autonomous tumor suppressor in HGSC. We demonstrate that CCDC80, localized to the nucleus, significantly reduces HGSC tumor growth and metastasis in vivo in a mouse model. Notably, CCDC80 exerts its function by suppressing the expression of the immune checkpoint protein B7-H3. However, in HGSC, B7-H3 is predominantly cytoplasmic and promotes HGSC proliferation and migration independent of its immune role. Additionally, PAX8 positively regulates B7-H3 expression in a CCDC80-independent manner, underscoring the multifaceted oncogenic role of PAX8. This study highlights the complex regulatory network involving PAX8, CCDC80, and B7-H3 in HGSC progression. Targeting this signaling pathway may provide a novel therapeutic strategy to improve treatment outcomes for patients with epithelial ovarian cancer. B7-H3, which is currently targeted in clinical trials, shows promise as HGSC target for therapy.