Fan Mingliang, Liu Ke, Shi Yonggang, Hao Jie, Qiu Haifeng, Liang Yan
Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Exp Cell Res. 2025 Sep 1;452(1):114751. doi: 10.1016/j.yexcr.2025.114751. Epub 2025 Sep 13.
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.
卵巢癌是一种在全球范围内具有高度致死性的妇科恶性肿瘤，主要归因于诊断延迟和化疗耐药。已确定Nedd4结合蛋白3（N4BP3）在多种癌症的发生发展中发挥作用。然而，其在卵巢癌中的作用仍不清楚。通过生物信息学分析，研究了N4BP3在卵巢癌中的表达谱及其与患者预后的关系。在卵巢癌细胞系中证实了N4BP3的表达。随后，通过调控N4BP3的表达来研究其对卵巢癌细胞恶性表型的影响。此外，建立了紫杉醇（PTX）耐药细胞系，以研究N4BP3对PTX耐药性的影响。进一步在体内分析了N4BP3对肿瘤生长和PTX耐药性的影响。利用生物信息学分析、免疫共沉淀和蛋白质印迹法探索了N4BP3的潜在作用机制。我们发现N4BP3在卵巢癌组织中高表达，N4BP3表达较高的患者总生存期和无进展生存期较短。N4BP3在卵巢癌细胞系中的表达较高，在PTX耐药细胞中的表达更高。上调N4BP3可显著促进卵巢癌细胞的增殖和侵袭，并提高其对PTX的耐药性，而下调N4BP3则产生相反的效果。在异种移植小鼠模型中，沉默N4BP3可抑制肿瘤生长并降低PTX耐药性。机制上，N4BP3通过与XPO1结合激活Wnt/β-连环蛋白信号通路。综上所述，N4BP3通过与XPO1相互作用激活Wnt/β-连环蛋白信号通路，促进卵巢癌进展和PTX耐药。N4BP3可能是治疗卵巢癌的一个潜在治疗靶点。
