NUF2 overexpression contributes to epithelial ovarian cancer progression via ERBB3-mediated PI3K-AKT and MAPK signaling axes

Introduction NDC80 kinetochore complex component (NUF2) is upregulated and plays an important role in various human cancers. However, the function and mechanism of NUF2 in epithelial ovarian cancer (EOC) remain unclear. Methods NUF2 expression was detected in EOC tissues and cell lines. The effects of NUF2 downregulation on cell proliferation, migration and invasion in EOC were analyzed by CCK-8 and Transwell assays. Meanwhile, the effect of NUF2 downregulation on tumor growth in vivo was determined by xenograft tumor models. The mechanisms by which NUF2 regulates EOC progression were detected by RNA sequencing and a series of in vitro assays. Results We showed that NUF2 was significantly upregulated in EOC tissues and cell lines, and high NUF2 expression was associated with FIGO stage, pathological grade and poor EOC prognosis. NUF2 downregulation decreased cell proliferation, migration, invasion and tumor growth in nude mice. RNA sequencing studies showed that NUF2 knockdown inhibited several genes enriched in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways. Erb-B2 receptor tyrosine kinase 3 (ERBB3) was the key factor involved in both of the above pathways. We found that ERBB3 silencing could inhibit EOC progression and repress activation of the PI3K-AKT and MAPK signaling pathways. Furthermore, the exogenous overexpression of ERBB3 partially reversed the inhibitory effects on EOC progression induced by NUF2 downregulation, while LY294002 and PD98059 partially reversed the effects of ERBB3 upregulation. Conclusion These results showed that NUF2 promotes EOC progression through ERBB3-induced activation of the PI3K-AKT and MAPK signaling axes. These findings suggest that NUF2 might be a potential therapeutic target for EOC.