The carcinogenesis of esophageal squamous cell cancer is positively regulated by USP13 through WISP1 deubiquitination.

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
BioFactors Pub Date : 2024-10-29 DOI:10.1002/biof.2139
An Wang, Youbo Wang, Qinyun Ma, Xiaofeng Chen
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引用次数: 0

Abstract

The objective was to determine whether USP13 stabilizes WISP1 protein and contributes to tumorigenicity and metastasis in ESCC through the Wnt/CTNNB1 signaling pathway. ESCC cell lines (KYSE150 and TE10) were treated with the proteasome inhibitor MG-132, followed by siRNA screening of deubiquitinases (DUBs) to identify regulators of WISP1. Mass spectrometry, immunoprecipitation, and in vitro functional assays were conducted to explore the interaction between USP13 and WISP1 and to assess the effects of USP13 downregulation on cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and apoptosis. Additionally, in vivo experiments using mouse models were performed to evaluate the impact of USP13 knockdown on tumor growth and metastasis. USP13 was identified as a key regulator of WISP1, stabilizing its protein levels through deubiquitination. Downregulation of USP13 resulted in reduced WISP1 protein stability, decreased cell proliferation, migration, and EMT, and increased apoptosis in vitro. In vivo, USP13 knockdown significantly inhibited tumor growth and lung metastasis. WISP1 overexpression in USP13-knockdown cells partially rescued these phenotypes, confirming the functional role of the USP13/WISP1 axis. Furthermore, knockdown of USP13 or WISP1 impaired the activation of the Wnt/CTNNB1 signaling pathway and reduced immune checkpoint marker expression, indicating a mechanism by which USP13 promotes immune evasion in ESCC. USP13 stabilizes WISP1 through deubiquitination, enhancing ESCC progression by activating the Wnt/CTNNB1 pathway and promoting immune evasion, making USP13 a potential therapeutic target in ESCC.

食管鳞状细胞癌的发生受 USP13 通过 WISP1 去泛素化的正向调控。
研究的目的是确定 USP13 是否能稳定 WISP1 蛋白,并通过 Wnt/CTNNB1 信号通路促进 ESCC 的致瘤性和转移。用蛋白酶体抑制剂 MG-132 处理 ESCC 细胞系(KYSE150 和 TE10),然后用 siRNA 筛选去泛素酶 (DUB),以确定 WISP1 的调节因子。研究人员进行了质谱分析、免疫沉淀和体外功能测试,以探索 USP13 与 WISP1 之间的相互作用,并评估 USP13 下调对细胞增殖、迁移、侵袭、上皮-间质转化(EMT)和凋亡的影响。此外,还利用小鼠模型进行了体内实验,以评估 USP13 下调对肿瘤生长和转移的影响。研究发现,USP13 是 WISP1 的关键调控因子,通过去泛素化稳定 WISP1 蛋白水平。下调 USP13 会导致 WISP1 蛋白稳定性降低,细胞增殖、迁移和 EMT 减少,体外凋亡增加。在体内,敲除 USP13 能显著抑制肿瘤生长和肺转移。在 USP13 敲除的细胞中过量表达 WISP1 可部分修复这些表型,证实了 USP13/WISP1 轴的功能作用。此外,敲除 USP13 或 WISP1 会影响 Wnt/CTNNB1 信号通路的激活,并降低免疫检查点标记物的表达,这表明 USP13 在 ESCC 中促进免疫逃避的机制。USP13通过去泛素化稳定WISP1,通过激活Wnt/CTNNB1通路和促进免疫逃避来加强ESCC的进展,从而使USP13成为ESCC的潜在治疗靶点。
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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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