SNCA 与免疫浸润相关，可作为肺腺癌的预后生物标志物。
SNCA correlates with immune infiltration and serves as a prognostic biomarker in lung adenocarcinoma.
机构信息
Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, 650118, China.
Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
出版信息
BMC Cancer. 2022 Apr 14;22(1):406. doi: 10.1186/s12885-022-09289-7.
BACKGROUND
The SNCA gene is a critical gene in Parkinson's disease (PD) pathology. Accumulating evidence indicates that SNCA is involved in tumorigenesis; however, the role of SNCA in lung adenocarcinoma (LUAD) remains unclear. This study aimed to explore the potential value of SNCA as a prognostic and diagnostic molecular marker in LUAD.
METHODS
In this study, we explored the expression pattern, prognostic value, and promoter methylation status of SNCA in LUAD based on Oncomine, UALCAN, and Kaplan-Meier Plotter. Then, using TIMER, we investigated the correlation between SNCA expression and immune infiltration. And cBioPortal were used to analysis the correlation between SNCA expression and immune checkpoint. The transcriptome data of A549 cells overexpressing SNCA were used to further study the potential immune role of SNCA in LUAD. The effect of SNCA on proliferation of A549 cells were evaluated by CCK-8, EdU and colony formation. Finally, LUAD cell lines treated with 5-aza-dC were used to explore the correlation between increased promoter methylation and downregulated mRNA expression of SNCA.
RESULTS
In general, the expression level of SNCA in LUAD tissue was lower than that in normal tissue, and high expression of SNCA was related to better prognosis. There were significant positive correlations between SNCA expression and immune infiltrations, including CD8+ T cells, macrophages, neutrophils, dendritic cells, B cells, and CD4+ T cells, and immune checkpoints, suggesting that immune infiltration was one of the reasons for the influence of SNCA on prognosis in LUAD. The transcriptome data of A549 cells overexpressing SNCA were further used to screen the relevant immune-related genes regulated by SNCA. Enrichment analysis confirmed that SNCA participates in the PI3K-AKT signaling pathway and other key tumor signaling pathways and regulates the expression of MAPK3, SRC, PLCG1, and SHC1. Cellular proliferation assay showed that SNCA could inhabit the growth of A549 cells via inhibiting activity of PI3K/AKT/ mTOR pathway. Finally, analysis of the methylation level of SNCA promoter showed that the promoter methylation negatively correlated with mRNA level. The expression of SNCA in LUAD cell lines was significantly upregulated by treatment with 5-aza-dC.
CONCLUSION
High methylation of SNCA promoter in LUAD is one of the reasons for the downregulation of SNCA mRNA level. Given that SNCA could inhibit the proliferation of A549 cells and correlates with immune infiltrates, it may serve as a prognostic biomarker in LUAD.
背景
SNCA 基因是帕金森病（PD）病理学中的关键基因。越来越多的证据表明，SNCA 参与肿瘤发生；然而，SNCA 在肺腺癌（LUAD）中的作用尚不清楚。本研究旨在探讨 SNCA 作为 LUAD 预后和诊断分子标志物的潜在价值。
方法
本研究基于 Oncomine、UALCAN 和 Kaplan-Meier Plotter 探讨了 SNCA 在 LUAD 中的表达模式、预后价值和启动子甲基化状态。然后，我们使用 TIMER 研究了 SNCA 表达与免疫浸润之间的相关性。并使用 cBioPortal 分析了 SNCA 表达与免疫检查点之间的相关性。使用过表达 SNCA 的 A549 细胞的转录组数据进一步研究了 SNCA 在 LUAD 中的潜在免疫作用。通过 CCK-8、EdU 和集落形成实验评估 SNCA 对 A549 细胞增殖的影响。最后，使用 5-aza-dC 处理 LUAD 细胞系，以探讨启动子甲基化增加与 SNCA mRNA 表达下调之间的相关性。
结果
总体而言，LUAD 组织中 SNCA 的表达水平低于正常组织，高表达 SNCA 与更好的预后相关。SNCA 表达与免疫浸润之间存在显著的正相关，包括 CD8+T 细胞、巨噬细胞、中性粒细胞、树突状细胞、B 细胞和 CD4+T 细胞，以及免疫检查点，这表明免疫浸润是 SNCA 影响 LUAD 预后的原因之一。进一步使用过表达 SNCA 的 A549 细胞的转录组数据筛选由 SNCA 调节的相关免疫相关基因。富集分析证实 SNCA 参与 PI3K-AKT 信号通路和其他关键肿瘤信号通路，并调节 MAPK3、SRC、PLCγ1 和 SHC1 的表达。细胞增殖实验表明，SNCA 可以通过抑制 PI3K/AKT/mTOR 通路的活性抑制 A549 细胞的生长。最后，对 SNCA 启动子的甲基化水平进行分析，结果表明启动子甲基化与 mRNA 水平呈负相关。用 5-aza-dC 处理 LUAD 细胞系后，SNCA 的表达明显上调。
结论
LUAD 中 SNCA 启动子的高甲基化是 SNCA mRNA 水平下调的原因之一。鉴于 SNCA 可以抑制 A549 细胞的增殖并与免疫浸润相关，它可能作为 LUAD 的预后生物标志物。
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