文献类型：期刊文献

英文题名：JOSD1 stabilizes SULF1 to activate Wnt7B-FZD1 signaling in gastric cancer

作者：Liu, Lixin[1,2,3];Ma, Zhijian[4];Zhang, Yaqing[5];Ye, Zhenzhen[6];Li, Hongbin[7];Shi, Wengui[8];Jiao, Zuoyi[9]

第一作者：Liu, Lixin

通信作者：Jiao, ZY[1]

机构：[1]Lanzhou Univ, Hosp & Clin Med Sch 2, Lanzhou 730030, Peoples R China;[2]Lanzhou Univ, Lanzhou 730030, Peoples R China;[3]Lanzhou Univ, Hosp 1, Dept Thorac Surg, Lanzhou 730030, Peoples R China;[4]Sun Yat Sen Univ, Canc Ctr, Dept Expt Res, Guangzhou 510060, Peoples R China;[5]Gansu Prov Matern & Child care Hosp, Dept Gynecol, Lanzhou 730050, Peoples R China;[6]Gansu Univ Chinese Med, Sch Clin Med 1, Lanzhou 730030, Peoples R China;[7]Lanzhou Univ Technol, Sch Life Sci & Engn, Lanzhou 730050, Peoples R China;[8]Lanzhou Univ, Hosp 2, Cuiying Biomed Res Ctr, Lanzhou 730030, Peoples R China;[9]Lanzhou Univ, Hosp 2, Dept Gen Surg, 82 Cuiyingmen, Lanzhou 730030, Gansu, Peoples R China

第一机构：Lanzhou Univ, Hosp & Clin Med Sch 2, Lanzhou 730030, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Hosp 2, Dept Gen Surg, 82 Cuiyingmen, Lanzhou 730030, Gansu, Peoples R China.

年份：2026

卷号：69

外文期刊名：TRANSLATIONAL ONCOLOGY

收录：;Scopus(收录号：2-s2.0-105038748490);WOS:【SCI-EXPANDED(收录号:WOS:001775138900001)】；

基金：Funding This work was supported by National Natural Science Foundation of Gansu province (No. 26JRRA335) , Key Research and Development Program of Gansu Province (No. 26YFFA004) , and Lanzhou University Student Innovation and Entrepreneurship Action Plan (No. 20260060199, No. 20260060068) .

语种：英文

外文关键词：Gastric cancer; JOSD1; SULF1; Deubiquitination; Wnt/(3-catenin; Epithelial-Mesenchymal transition

摘要：Background: Aberrant activation of Wnt/(3-catenin signaling is a major driver of Gastric cancer (GC) progression. However, the upstream mechanisms that sustain receptor-ligand engagement within this pathway remain insufficiently characterized. Methods: Comprehensive analyses of GC cohorts and tissue microarrays were performed to evaluate Josephin Domain Containing 1 (JOSD1) expression and its clinical significance. The impact of JOSD1 on cell proliferation, migration, invasion, apoptosis, and epithelial mesenchymal transition (EMT) was examined in vitro employing CCK-8, colony formation, Transwell, flow cytometry, Western blotting, and immunofluorescence assays. Subcutaneous xenograft models were used to assess the effects of JOSD1 on tumor growth in vivo. Mechanistic studies, including co-immunoprecipitation, ubiquitination, and rescue experiments, were employed to elucidate the molecular relationship between JOSD1, Heparan sulfate 6-O-endosulfatase 1 (SULF1), and the Wnt7B/FZD1/ (3-catenin signaling axis. Results: JOSD1 expression was markedly elevated in GC tissues (logy FC > 1, FDR < 0.05) and correlated with advanced stage (P < 0.05) and poor patient prognosis (HR > 1, log-rank P < 0.05). Functionally, JOSD1 promoted GC cell proliferation, invasion, and EMT, while inhibiting apoptosis (P < 0.05). Mechanistically, JOSD1 functioned as a critical deubiquitinase that stabilized SULF1. Stabilized SULF1 directly bound the Wnt coreceptor Frizzled class receptor 1 (FZD1) and facilitated Wnt7B-FZD1 complex formation (P < 0.05), thereby activating canonical Wnt/(3-catenin signaling and inducing (3-catenin nuclear accumulation (P < 0.05). Ubiquitination and rescue assays confirmed that JOSD1-driven oncogenic effects were strictly dependent on SULF1 stabilization (P < 0.05). In vivo modulation of the JOSD1-SULF1 axis significantly altered tumor growth, apoptotic activity, EMT marker expression, and Wnt pathway activation (P < 0.05). Conclusion: JOSD1 functions as a critical deubiquitinase that stabilizes SULF1 to activate Wnt/(3-catenin signaling, thereby driving GC progression. Targeting the JOSD1-SULF1-Wnt7B/FZD1/(3-catenin axis may provide a promising therapeutic strategy for patients with GC.