Abstract
Objective: The therapeutic options for patients with advanced endometrial carcinoma (EC) were still limited and the prognosis remained unfavorable. F-box and leucine-rich repeat protein 18 (FBXL18), belonging to the F-box protein family, was frequently altered in human cancer, while its functional role and underlying mechanisms in EC were largely unexplored. Methods: The expression of FBXL18 in EC tissues and cells were explored using data mining strategies and further experiments. Multiple in vitro assays, including CCK-8, colony formation, wound healing, and Transwell invasion assays, were performed to assess the function of FBXL18 on cell proliferation, migration, and invasion. Bioinformatic analyses, western blot, qRT-PCR, Co-immunoprecipitation and ubiquitination assays were employed to identify the downstream pathway and direct substrate of FBXL18. Results: FBXL18 was highly expressed in EC tissues and cell lines, and EC patients with high FBXL18 expression had poor clinical outcome. Loss- and gain-of-function assays showed that silencing FBXL18 suppressed EC cell proliferation, migration, and invasion, while overexpressing FBXL18 caused the opposite effects. Mechanistically, FBXL18 could physically interacted with DUSP16, a dual specificity phosphatase, leading to its ubiquitination and degradation, and thus activating JNK signaling pathway. Upregulation of DUSP16 in EC cells alleviated FBXL18 overexpression-induced activation of JNK signaling pathway, and reversed FBXL18 overexpression-mediated enhanced cell capacities of proliferation, migration, and invasion. Conclusion: In summary, our study had showcased the elevated expression, prognostic prediction performance, and the malignant tumor-promoting role of FBXL18 in EC. The novel mechanisms underlying this phenotype are that FBXL18 promotes the ubiquitination and degradation of DUSP16, and thus activates JNK/c-JUN signaling to facilitate EC progression.