Demethylation of the SFRP4 Promoter Drives Gastric Cancer Progression via the Wnt Pathway
Demethylation of the SFRP4 Promoter Drives Gastric Cancer Progression via the Wnt Pathway
复制标题
SFRP4启动子去甲基化通过Wnt途径驱动胃癌进展
DOI：
10.1158/1541-7786.mcr-20-0933
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发表时间：
2021-09-01
影响因子：
5.2
通讯作者：
Sun, Yihong
中科院分区：
文献类型：
--
作者：
Li, Haojie;Zhao, Junjie;Sun, Yihong
Wnt信号传导被认为是肿瘤发展的重要贡献者，并且已经报道被分泌的卷曲相关蛋白（SFRP）调节。然而，分泌型卷曲相关蛋白4（SFRP 4）在肿瘤发生中的作用仍然存在争议。我们的目标是探索其在胃癌中的生物学功能。利用基因表达综合数据集（GEO）进行基因组分析，寻找胃癌不同TNM分期的差异基因表达。采用免疫组化方法检测胃癌组织中SFRP 4的表达与临床病理特征的关系。通过CCK-8、集落形成、细胞凋亡、细胞周期和体内移植瘤模型评价SFRP 4对肿瘤进展的影响。采用甲基化定量分析法检测胃癌组织中SFRPs的甲基化状态。SFRP 4在进展期胃癌中表达最高。SFRP 4在胃癌组织中的高表达与肿瘤的浸润和转移有关，是胃癌患者预后不良的指标。体内外研究表明，SFRP 4可促进肿瘤生长，而IWR-1可抑制SFRP 4过表达介导的肿瘤生长。机制探索发现，SFRP 4通过降低启动子甲基化而过表达，从而竞争性拮抗SFRP 1对胃癌Wnt通路激活和肿瘤进展的抑制作用。结论：胃癌组织中SFRP 4基因甲基化水平降低，表达上调。肿瘤内SFRP 4高表达可激活Wnt通路，促进肿瘤进展，并预测胃癌患者的生存不良。
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.