Stomatin plays a suppressor role in non-small cell lung cancer metastasis
Stomatin plays a suppressor role in non-small cell lung cancer metastasis
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Stomatin在非小细胞肺癌转移中发挥抑制作用
DOI：
10.21147/j.issn.1000-9604.2019.06.09
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发表时间：
2019-12-01
影响因子：
5.1
通讯作者：
Ma, Jie
中科院分区：
文献类型：
--
作者：
An, Huaying;Ma, Xiao;Ma, Jie
目的转移是肺癌高死亡率的主要原因之一。DNA甲基化异常是转移性肺癌中常见的事件。我们的目的是确定转移相关基因的新表观遗传调控，并描述其对肺癌进展的影响。方法整合GEO数据库中的基因表达数据，筛选与非小细胞肺癌（NSCLC）转移相关的基因。我们通过分析去甲基化基因的表达谱获得了表观遗传调控的候选基因。通过重叠分析，获得了表观遗传学调节的转移相关基因。采用Kaplan-Meier生存率（KM生存率）评估口腔癌素治疗肺癌的总生存率（OS）。免疫组化（IHC）进行，以确定气孔蛋白和转移相关的临床指标之间的关联。在体外和体内试验进行了调查的潜在作用，气孔蛋白在转移。采用Sequenom MassARRAY甲基化定量分析和Western blot方法，探讨转化生长因子β1（TGFβ1）对气孔蛋白的调控机制。结果一系列生物信息学分析表明，stomatin是受DNA甲基化调控的转移相关基因。KM回归分析显示，气孔蛋白与肺癌的OS呈正相关。免疫组化分析表明，stomatin表达的降低与TNM分期的进展有关。功能丧失和获得实验表明，气孔蛋白可以抑制非小细胞肺癌细胞的迁移和侵袭。此外，TGFβ1在上皮-间充质转化（EMT）过程中抑制了气孔蛋白的表达。在晚期III期肺肿瘤样品中也验证了气孔蛋白和TGFβ1之间的负相关性。TGFβ1抑制气孔蛋白的潜在机制部分是由于DNA甲基化。结论我们的研究结果表明，气孔蛋白可能是一个目标的表观遗传调控，并可用于预防转移性疾病。
Objective Metastasis is one of the key causes of high mortality in lung cancer. Aberrant DNA methylation is a common event in metastatic lung cancer. We aimed to identify new epigenetic regulation of metastasis-associated genes and characterize their effects on lung cancer progression. Methods We screened genes associated with non-small cell lung cancer (NSCLC) metastasis by integrating datasets from the Gene Expression Omnibus (GEO) database. We obtained epigenetic-regulated candidate genes by analyzing the expression profile of demethylation genes. By overlapping analysis, epigenetically modulated metastasis-associated genes were obtained. Kaplan-Meier plotter (KM plotter) was utilized to assess the overall survival (OS) of stomatin in lung cancer. Immunohistochemistry (IHC) was conducted to determine the association between stomatin and metastasis-associated clinical indicators. Both in vitro and in vivo assays were performed to investigate the potential role of stomatin in metastasis. The regulation mechanisms of transforming growth factor β1 (TGFβ1) on stomatin were determined by Sequenom MassARRAY quantitative methylation and western blot assays. Results A series of bioinformatic analyses revealed stomatin as the metastasis-associated gene regulated by DNA methylation. The KM plotter analysis showed a positive association between stomatin and the OS of lung cancer. IHC analysis indicated that the decreased stomatin expression is linked with advanced TNM stage. Loss- and gain-of-function experiments displayed that stomatin could inhibit the migration and invasion of NSCLC cells. Furthermore, TGFβ1 repressed stomatin expression during epithelial-to-mesenchymal transition (EMT). The negative correlation between stomatin and TGFβ1 was also validated in advanced stage III lung tumor samples. The underlying mechanism by which TGFβ1 inhibits stomatin is due in part to DNA methylation. Conclusions Our results suggest that stomatin may be a target for epigenetic regulation and can be used to prevent metastatic diseases.