N4BP3 promotes ovarian cancer progression and paclitaxel resistance by activating the Wnt/β-catenin signaling through interaction with XPO1
Ovarian cancer is a highly lethal gynecological malignancy worldwide, primarily attributed to late diagnosis and chemoresistance. The Nedd4-binding protein 3 (N4BP3) has been identified to function in the development of several cancers. However, its role in ovarian cancer remains unclear. The expression profile of N4BP3 and its association with patients' prognosis in ovarian cancer was analyzed through bioinformatic analysis. N4BP3 expression was confirmed in ovarian cancer cell lines. Subsequently, N4BP3 expression was manipulated to investigate its effects on the malignant phenotypes of ovarian cancer cells. Furthermore, paclitaxel (PTX)-resistant cell lines were established to examine N4BP3's influence on PTX resistance. The effects of N4BP3 on tumor growth and PTX resistance were further analyzed in vivo. The potential mechanisms of N4BP3 were explored using bioinformatic analysis, co-immunoprecipitation, and Western blot. We found that N4BP3 was highly expressed in ovarian cancer tissues, and patients with higher N4BP3 expression exhibited shorter overall survival and progression-free survival. N4BP3 expression was higher in ovarian cancer cell lines, with even higher levels in PTX-resistant cells. Upregulation of N4BP3 significantly promoted the proliferation and invasion, and elevated PTX resistance in ovarian cancer cells, while its downregulation had the opposite effects. Silencing of N4BP3 inhibited tumor growth and decreased PTX resistance in a xenograft mouse model. Mechanistically, N4BP3 activated the Wnt/β-catenin signaling through binding to XPO1. Taken together, N4BP3 promotes ovarian cancer progression and PTX resistance by activating the Wnt/β-catenin signaling through interaction with XPO1. N4BP3 may serve as a potential therapeutic target for the treatment of ovarian cancer.