Pi Jie, Wang Yong, Zhao Yuzi, Yang Jing
Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Cancer Cell Int. 2025 May 17;25(1):180. doi: 10.1186/s12935-025-03808-9.
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.
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.
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.
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.
晚期子宫内膜癌（EC）患者的治疗选择仍然有限，预后依然不佳。F-box和富含亮氨酸重复序列蛋白18（FBXL18）属于F-box蛋白家族，在人类癌症中经常发生改变，但其在EC中的功能作用和潜在机制在很大程度上尚未被探索。
利用数据挖掘策略和进一步实验探究FBXL18在EC组织和细胞中的表达。进行了多种体外实验，包括CCK-8、集落形成、伤口愈合和Transwell侵袭实验，以评估FBXL18对细胞增殖、迁移和侵袭的功能。采用生物信息学分析、蛋白质免疫印迹、qRT-PCR、免疫共沉淀和泛素化实验来鉴定FBXL18的下游途径和直接底物。
FBXL18在EC组织和细胞系中高表达，FBXL18高表达的EC患者临床预后较差。功能缺失和功能获得实验表明，沉默FBXL18可抑制EC细胞增殖、迁移和侵袭，而过表达FBXL18则产生相反的效果。机制上，FBXL18可与双特异性磷酸酶DUSP16发生物理相互作用，导致其泛素化和降解，从而激活JNK信号通路。在EC细胞中上调DUSP16可减轻FBXL18过表达诱导的JNK信号通路激活，并逆转FBXL过表达介导的增强的细胞增殖、迁移和侵袭能力。
总之，我们的研究展示了FBXL18在EC中的表达升高、预后预测性能以及促进恶性肿瘤的作用。这种表型的新机制是FBXL18促进DUSP16的泛素化和降解，从而激活JNK/c-JUN信号以促进EC进展。
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