Objective: CA125/MUC16 is an O-glycosylated protein that is expressed on the surfaces of ovarian epithelial cells. This molecule is a widely used tumor-associated marker for diagnosis of ovarian cancer. Recently, CA125 was shown to be involved in ovarian cancer metastasis. The purpose of this study was to investigate the mechanism of CA125 during ovarian cancer metastasis./nMethods: We analyzed the Oncomine and CSIOVDB databases to determine the expression levels of DKK1 in ovarian cancer. DKK1 expression levels were upregulated or downregulated and applied with CA125 to Transwell and Western blot assays to ascertain the underlying mechanism by which CA125 stimulates cell migration via the SGK3/FOXO3 pathway. Anti-mesothelin antibodies (anti-MSLN) were used to block CA125 stimulation. Then the expression levels of DKK1were tested by enzyme-linked immunosorbent assay (ELISA) to eliminate the blocking effect of anti-MSLN to CA125 stimulation. Xenograft mouse models were used to detect the effects of CA125 and anti-MSLN on ovarian cancer metastasis in vivo./nResults: DKK1 levels were downregulated in ovarian tumor tissues according to the analyses of two databases and significantly correlated with FIGO stage, grade and disease-free survival in ovarian cancer patients. DKK1 levels were downregulated by CA125 stimulation in vitro. Overexpression of DKK1 reversed the ability of exogenous CA125 to mediate cell migration by activating the SGK3/FOXO3 signaling pathway. Anti-MSLN abrogated the DKK1 reduction and increased the apoptosis of ovarian cancer cells. The use of anti-MSLN in xenograft mouse models significantly reduced tumor growth and metastasis accelerated by CA125./nConclusions: These experiments revealed that the SGK3/FOXO3 pathway was activated, wherein decreased expression of DKK1 was caused by CA125, which fuels ovarian cancer cell migration. Mesothelin is a potential therapeutic target for the treatment of ovarian cancer metastasis.

中文翻译：

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游离CA125通过结合间皮素降低DKK1表达并激活SGK3/FOXO3通路促进卵巢癌细胞迁移和肿瘤转移

目的： CA125/MUC16 是一种 O-糖基化蛋白，表达于卵巢上皮细胞表面。该分子是一种广泛使用的肿瘤相关标志物，用于诊断卵巢癌。最近，CA125 被证明与卵巢癌转移有关。本研究的目的是探讨CA125在卵巢癌转移过程中的作用机制。/n方法：我们分析了 Oncomine 和 CSIOVDB 数据库以确定 DKK1 在卵巢癌中的表达水平。DKK1 表达水平上调或下调，并与 CA125 一起应用于 Transwell 和蛋白质印迹分析，以确定 CA125 通过 SGK3/FOXO3 途径刺激细胞迁移的潜在机制。抗间皮素抗体（抗 MSLN）用于阻断 CA125 刺激。然后通过酶联免疫吸附试验（ELISA）检测DKK1的表达水平，以消除抗MSLN对CA125刺激的阻断作用。异种移植小鼠模型用于检测 CA125 和抗MSLN对体内卵巢癌转移的影响。/n结果：根据两个数据库的分析，DKK1水平在卵巢肿瘤组织中下调，并且与卵巢癌患者的FIGO分期、分级和无病生存率显着相关。体外CA125 刺激可下调 DKK1 水平。DKK1 的过表达通过激活 SGK3/FOXO3 信号通路逆转外源性 CA125 介导细胞迁移的能力。抗 MSLN 消除了 DKK1 的减少并增加了卵巢癌细胞的凋亡。在异种移植小鼠模型中使用抗 MSLN 可显着降低 CA125 加速的肿瘤生长和转移。/n结论：这些实验表明 SGK3/FOXO3 通路被激活，其中 DKK1 的表达降低是由 CA125 引起的，CA125 促进卵巢癌细胞迁移。间皮素是治疗卵巢癌转移的潜在治疗靶点。