Wnt signaling is believed to be an important contributor to tumor development and has been reported to be modulated by secreted frizzled-related proteins (SFRP). Nevertheless, the role of secreted frizzled-related protein 4 (SFRP4) in tumorigenesis remains controversial. We aim to explore its biological function in gastric cancer. Genomes analysis based on the Gene Expression Omnibus (GEO) dataset was used to find the differential gene expression between different tumor–node–metastasis (TNM) stages of gastric cancer. IHC was used to determine the relationship between SFRP4 expression and clinicopathologic characteristics in patients with gastric cancer. The influence of SFRP4 on tumor progression was evaluated by CCK-8, colony formation, cell apoptosis, and cell cycle in vitro , as well as xenograft model in vivo . The methylation status of SFRPs was examined in gastric cancer specimens by quantitative methylation analysis. SFRP4 was most upregulated in advanced gastric cancer. High intratumoral SFRP4 expression, which was associated with tumor invasion and metastasis, was also a poor prognostic indicator for patients with gastric cancer. In vitro and in vivo studies revealed that SFRP4 could promote tumor growth; however, IWR-1 could suppress tumor growth mediated by SFRP4 overexpression. Mechanistic exploration found that SFRP4 was overexpressed by the decrease of promoter methylation and thus could competitively antagonize the inhibitory effect of SFRP1 on Wnt pathway activation and tumor progression in gastric cancer. Implications: In gastric cancer, the expression of SFRP4 was upregulated by decreased methylation. High intratumoral SFRP4 expression could activate the Wnt pathway to promote tumor progression and predict poor survival of patients with gastric cancer.

中文翻译：

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SFRP4 启动子的去甲基化通过 Wnt 通路驱动胃癌进展

Wnt 信号传导被认为是肿瘤发展的重要贡献者，据报道它受分泌的卷曲相关蛋白 (SFRP) 的调节。然而，分泌的卷曲相关蛋白 4 (SFRP4) 在肿瘤发生中的作用仍然存在争议。我们旨在探索其在胃癌中的生物学功能。基于基因表达综合（GEO）数据集的基因组分析用于发现胃癌不同肿瘤-淋巴结-转移（TNM）阶段之间的差异基因表达。IHC 用于确定 SFRP4 表达与胃癌患者临床病理特征之间的关系。通过体外CCK-8、集落形成、细胞凋亡和细胞周期以及体内异种移植模型评估SFRP4对肿瘤进展的影响。通过定量甲基化分析检查胃癌标本中 SFRP 的甲基化状态。SFRP4 在晚期胃癌中上调最多。与肿瘤侵袭和转移相关的高肿瘤内 SFRP4 表达也是胃癌患者预后不良的指标。体外和体内研究表明，SFRP4 可以促进肿瘤生长；然而，IWR-1 可以抑制由 SFRP4 过表达介导的肿瘤生长。机制探索发现，SFRP4因启动子甲基化降低而过度表达，从而可以竞争性拮抗SFRP1对胃癌Wnt通路激活和肿瘤进展的抑制作用。启示：在胃癌中，SFRP4 的表达因甲基化减少而上调。