FBXL18 promotes endometrial carcinoma progression via destabilizing DUSP16 and thus activating JNK signaling pathway.

IF 6 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-05-17 DOI:10.1186/s12935-025-03808-9

Jie Pi, Yong Wang, Yuzi Zhao, Jing Yang

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引用次数: 0

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.

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FBXL18通过破坏DUSP16从而激活JNK信号通路促进子宫内膜癌进展。

目的：晚期子宫内膜癌（EC）患者的治疗选择仍然有限，预后仍然不利。F-box和富亮氨酸重复蛋白18 （FBXL18）属于F-box蛋白家族，在人类癌症中经常发生改变，而其在EC中的功能作用和潜在机制在很大程度上尚未被探索。方法：采用数据挖掘策略和进一步实验，探讨FBXL18在EC组织和细胞中的表达。通过CCK-8、菌落形成、伤口愈合和Transwell侵袭试验等多种体外实验，评估FBXL18对细胞增殖、迁移和侵袭的作用。采用生物信息学分析、western blot、qRT-PCR、共免疫沉淀和泛素化等方法鉴定FBXL18的下游途径和直接底物。结果：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细胞的增殖、迁移和侵袭，而过表达FBXL18则会产生相反的效果。机制上，FBXL18可与双特异性磷酸酶DUSP16物理相互作用，导致其泛素化和降解，从而激活JNK信号通路。EC细胞中DUSP16的上调可减轻FBXL18过表达诱导的JNK信号通路激活，逆转FBXL18过表达介导的细胞增殖、迁移和侵袭能力增强。结论：综上所述，我们的研究显示了FBXL18在EC中的表达升高、预后预测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信号通路，促进EC的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.