背景:胃癌(GC)预后较差,因为它具有高度侵袭性,然而,目前几乎没有有效的治疗方法。尽管蛋白质泛素化已被证明在胃癌的发展中起着复杂的作用,到目前为止,尚未确定有效的泛素化酶作为GC的治疗靶标。
方法:TCGA数据库用于GC中泛素特异性蛋白酶31(USP31)表达的生物信息学研究,和实验技术,包括西方印迹,qRT-PCR,和免疫组织化学,被用来证实调查结果。我们还剖析了GC患者USP31表达与临床预后的关系。我们进一步研究了USP31对增殖的影响,入侵,迁移,并通过集落形成在体外和体内对GC细胞进行糖酵解,CCK-8测定,Transwell腔室分析,细胞划痕试验,和细胞来源的异种移植物。此外,我们研究了USP31影响GC生物学发展的分子过程。
结果:USP31高表达的患者预后较差,因为USP31在GC中大量表达。因此,USP31通过与β-catenin结合降低Wnt/β-catenin途径的泛素化水平,从而激活糖酵解,最终促进GC增殖和侵袭性转移。
结论:USP31通过与β-catenin结合来抑制β-catenin的泛素化,刺激Wnt/β-catenin通路,激活糖酵解,加速了GC的生物学,这些都在这项工作中得到了证明。
BACKGROUND: Gastric cancer (GC) has a poor prognosis because it is highly aggressive, yet there are currently few effective therapies available. Although protein ubiquitination has been shown to play a complex role in the development of gastric cancer, to date, no efficient ubiquitinating enzymes have been identified as treatment targets for GC.
METHODS: The TCGA database was used for bioinformatic investigation of ubiquitin-specific protease 31 (
USP31) expression in GC, and experimental techniques, including Western blotting, qRT-PCR, and immunohistochemistry, were used to confirm the findings. We also analyzed the relationship between
USP31 expression and clinical prognosis in patients with GC. We further investigated the effects of
USP31 on the proliferation, invasion, migration, and glycolysis of GC cells in vitro and in vivo by using colony formation, CCK-8 assays, Transwell chamber assays, cell scratch assays, and cell-derived xenograft. Furthermore, we examined the molecular processes by which
USP31 influences the biological development of GC.
RESULTS: Patients with high
USP31 expression have a poor prognosis because
USP31 is abundantly expressed in GC. Therefore, USP31 reduces the level of ubiquitination of the Wnt/β-catenin pathway by binding to β-catenin, thereby activating glycolysis, which ultimately promotes GC proliferation and aggressive metastasis.
CONCLUSIONS: USP31 inhibits ubiquitination of β-catenin by binding to it, stimulates the Wnt/β-- catenin pathway, activates glycolysis, and accelerates the biology of GCs, which are all demonstrated in this work.