FUS-stabilized USP7 facilitates the bevacizumab resistance of ovarian cancer through deubiquitinating PTK2.

IF 3.7 2区医学 Q1 OBSTETRICS & GYNECOLOGY

Journal of Gynecologic Oncology Pub Date : 2025-07-30 DOI:10.3802/jgo.2026.37.e3

Xianping Wen, Ruocheng Xu, Ranran Li, Shuo Li, Guantai Ni

{"title":"FUS-stabilized USP7 facilitates the bevacizumab resistance of ovarian cancer through deubiquitinating PTK2.","authors":"Xianping Wen, Ruocheng Xu, Ranran Li, Shuo Li, Guantai Ni","doi":"10.3802/jgo.2026.37.e3","DOIUrl":null,"url":null,"abstract":"Objective: The emergence of drug resistance brings new challenges to the clinical management of ovarian cancer (OC) patients. This study aimed to explore the role and mechanism of ubiquitin-specific peptidase 7 (USP7) on the bevacizumab resistance of OC.Methods: The mRNA levels of USP7 and protein tyrosine kinase 2 (PTK2) were measured using quantitative real-time polymerase chain reaction. Western blot analysis was used for detecting the protein levels of USP7, PTK2 and fused in sarcoma (FUS). Cell resistance, proliferation, apoptosis, invasion and angiogenesis were determined by cell counting kit 8 assay, colony formation assay, flow cytometry, transwell assay and tube formation assay. Glucose consumption, lactate production, and ATP/ADP ratio were used to evaluate glycolysis. The interactions between USP7 and PTK2/FUS were detected by co-immunoprecipitation assay. Mice xenograft model was also constructed to explore USP7 roles in vivo.Results: USP7 was upregulated in OC tissues and bevacizumab-resistant cells. USP7 knockdown or its inhibitor P22077 inhibited the bevacizumab resistance of OC cells via suppressing cell growth, metastasis, angiogenesis and glycolysis. USP7 stabilized PTK2 protein expression via deubiquitinating. PTK2 overexpression reversed the effect of USP7 knockdown on the bevacizumab resistance of OC cells. Besides, FUS stabilized USP7 mRNA to regulate its protein level, and it could affect PTK2 expression by mediating USP7. USP7 knockdown enhanced the sensitivity of OC tumors to bevacizumab in vivo.Conclusion: FUS-stabilized USP7 enhanced the bevacizumab resistance of OC by deubiquitinating PTK2, providing a new idea for overcoming bevacizumab resistance in OC.","PeriodicalId":15868,"journal":{"name":"Journal of Gynecologic Oncology","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gynecologic Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3802/jgo.2026.37.e3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OBSTETRICS & GYNECOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective: The emergence of drug resistance brings new challenges to the clinical management of ovarian cancer (OC) patients. This study aimed to explore the role and mechanism of ubiquitin-specific peptidase 7 (USP7) on the bevacizumab resistance of OC.

Methods: The mRNA levels of USP7 and protein tyrosine kinase 2 (PTK2) were measured using quantitative real-time polymerase chain reaction. Western blot analysis was used for detecting the protein levels of USP7, PTK2 and fused in sarcoma (FUS). Cell resistance, proliferation, apoptosis, invasion and angiogenesis were determined by cell counting kit 8 assay, colony formation assay, flow cytometry, transwell assay and tube formation assay. Glucose consumption, lactate production, and ATP/ADP ratio were used to evaluate glycolysis. The interactions between USP7 and PTK2/FUS were detected by co-immunoprecipitation assay. Mice xenograft model was also constructed to explore USP7 roles in vivo.

Results: USP7 was upregulated in OC tissues and bevacizumab-resistant cells. USP7 knockdown or its inhibitor P22077 inhibited the bevacizumab resistance of OC cells via suppressing cell growth, metastasis, angiogenesis and glycolysis. USP7 stabilized PTK2 protein expression via deubiquitinating. PTK2 overexpression reversed the effect of USP7 knockdown on the bevacizumab resistance of OC cells. Besides, FUS stabilized USP7 mRNA to regulate its protein level, and it could affect PTK2 expression by mediating USP7. USP7 knockdown enhanced the sensitivity of OC tumors to bevacizumab in vivo.

Conclusion: FUS-stabilized USP7 enhanced the bevacizumab resistance of OC by deubiquitinating PTK2, providing a new idea for overcoming bevacizumab resistance in OC.

查看原文本刊更多论文

fus稳定的USP7通过去泛素化PTK2促进卵巢癌的贝伐单抗耐药。

目的：耐药的出现给卵巢癌患者的临床治疗带来了新的挑战。本研究旨在探讨泛素特异性肽酶7 （USP7）在OC贝伐单抗耐药中的作用及机制。方法：采用实时定量聚合酶链反应法检测USP7和蛋白酪氨酸激酶2 (PTK2) mRNA表达水平。Western blot检测肉瘤（FUS）中USP7、PTK2和融合蛋白的表达水平。采用细胞计数试剂盒8法、集落形成法、流式细胞术、transwell法和成管法检测细胞的耐药、增殖、凋亡、侵袭和血管生成。葡萄糖消耗、乳酸生成和ATP/ADP比值用于评价糖酵解。采用共免疫沉淀法检测USP7与PTK2/FUS的相互作用。我们还构建了小鼠异种移植模型来探索USP7在体内的作用。结果：USP7在OC组织和贝伐单抗耐药细胞中表达上调。USP7敲低或其抑制剂P22077通过抑制细胞生长、转移、血管生成和糖酵解抑制OC细胞对贝伐单抗的耐药。USP7通过去泛素化稳定PTK2蛋白的表达。PTK2过表达逆转了USP7敲低对OC细胞贝伐单抗耐药的影响。FUS稳定USP7 mRNA，调节其蛋白水平，并通过介导USP7影响PTK2表达。在体内，USP7敲低增强了OC肿瘤对贝伐单抗的敏感性。结论：fus稳定的USP7通过去泛素化PTK2增强OC的贝伐单抗耐药，为OC克服贝伐单抗耐药提供了新的思路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Gynecologic Oncology ONCOLOGY-OBSTETRICS & GYNECOLOGY

CiteScore

6.00

自引率

2.60%

发文量

审稿时长

>12 weeks

期刊介绍： The Journal of Gynecologic Oncology (JGO) is an official publication of the Asian Society of Gynecologic Oncology. Abbreviated title is ''J Gynecol Oncol''. It was launched in 1990. The JGO''s aim is to publish the highest quality manuscripts dedicated to the advancement of care of the patients with gynecologic cancer. It is an international peer-reviewed periodical journal that is published bimonthly (January, March, May, July, September, and November). Supplement numbers are at times published. The journal publishes editorials, original and review articles, correspondence, book review, etc.