NEDD4 facilitates the progression of endometrial carcinoma by enhancing PAMR1 protein degradation through ubiquitination

Abstract

Endometrial carcinoma (EC) is an epithelial malignant neoplasm that frequently appears in postmenopausal and perimenopausal women. PAMR1 is related to the prognosis of EC. Here, we probed into the significance of PAMR1 in EC progression and its acting mechanism. In silico analysis was conducted to identify the differentially expressed gene PAMR1 and its upstream gene NEDD4 in EC, followed by the determination of their expression in EC tissues and cells. The gene expression, cell proliferation, angiogenesis, migration, invasion, and apoptosis were examined after ectopic expression or knockdown experiments. The interaction between NEDD4 and PAMR1 and the level of PAMR1 ubiquitination were examined. The injection of Ishikawa cell suspensions into nude mice was carried out to establish a tumor xenograft model, validating the roles of PAMR1 and NEDD4 in EC. EC cells exhibited high NEDD4 expression and low PAMR1 expression. NEDD4 knockdown or PAMR1 overexpression suppressed the invasive, migrating, angiogenic, and proliferative properties of EC cells while promoting apoptosis. NEDD4 facilitated PAMR1 protein degradation through ubiquitination. Deletion of PAMR1 abolished the inhibitory effects of NEDD4 knockdown on the malignant behaviors of EC cells. Furthermore, NEDD4 knockdown restrained EC growth in nude mice by increasing PAMR1 protein expression. NEDD4 facilitated EC progression by enhancing PAMR1 protein degradation through ubiquitination.

Graphical Abstract