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Epigenetic silencing of microRNA-204 by Helicobacter pylori augments the NF-κB signaling pathway in gastric cancer development and progression.
幽门螺杆菌对 microRNA-204 的表观遗传沉默增强了胃癌发生和发展中 NF-κ b 信号通路。
- 影响因子：4.33
- DOI：10.1093/carcin/bgz143
- 作者列表："Chen P","Guo H","Wu X","Li J","Duan X","Ba Q","Wang H
- 发表时间：2020-06-17
Abstract
:Helicobacter pylori infection induces gastric cancer (GC) development through a progressive cascade; however, the roles of the microRNAs that are involved in the cascade and the underlying mechanisms are still unclear. Here, we found that microRNA-204 was suppressed in gastric mucosal cells in response to H.pylori infection and downregulated in GC tissues due to aberrant methylation of the promoter of its host gene, TRPM3. Helicobacter pylori induced a progressive downregulation of microRNA-204 from superficial gastritis to intestinal metaplasia, with an accompanying increment of the methylated levels of CpG sites in the TRPM3 promoter. With the GC cellular models of AGS, MGC-803 or BGC-823, we found that microRNA-204 suppressed the tumor necrosis factor (TNF)-α-induced activation of NF-κB signaling pathways and, in animal models, inhibited tumor growth and metastasis. The conditional supernatant of microRNA-204 overexpression GC cells led to reduced tube formation of human umbilical vein endothelial cells. A target gene for microRNA-204 was BIRC2, and in GC cells, BIRC2 knockdown recapitulated the biological phenotype of microRNA-204 overexpression. BIRC2 overexpression promoted the metastasis of GC cells and rescued the inhibition activities of microRNA-204 on cell migration and the NF-κB signaling pathway. Moreover, lower microRNA-204 and higher BIRC2 expression levels were associated with a poorer prognosis of GC patients. These results demonstrate that epigenetic silencing of microRNA-204 induced by H.pylori infection augments the NF-κB signaling pathway in H.pylori-induced gastritis and GC, potentially providing novel intervention targets for these diseases. MicroRNA-204 was epigenetically down-regulated by H. pylori infection in gastric mucosal cells. It led to enhanced BIRC2 expression level and BIRC2/TNF-a/NF-kB signaling pathway activities, which promoted angiogenesis and metastasis of gastric cancer cells.
摘要
幽门螺杆菌感染通过进行性级联反应诱导胃癌 (GC) 发展; 然而，参与级联反应的 microRNAs 的作用和潜在机制仍不清楚。在这里，我们发现 microRNA-204 在胃黏膜细胞中受到 H.pylori 感染的抑制，而在 GC 组织中由于其宿主基因 trpm3 启动子的异常甲基化而下调。幽门螺杆菌诱导从浅表性胃炎到肠化生的 microRNA-204 进行性下调，伴随着 TRPM3 启动子中 CpG 位点甲基化水平的增加。通过 AGS 、 MGC-803 或 BGC-823 的 GC 细胞模型，我们发现 microRNA-204 抑制肿瘤坏死因子 (TNF)-α 诱导的 NF-κ b 信号通路的激活,在动物模型中，抑制肿瘤生长和转移。MicroRNA-204 过表达 GC 细胞的条件上清液导致人脐静脉内皮细胞管形成减少。MicroRNA-204 的靶基因是 BIRC2，在 GC 细胞中，BIRC2 敲除概括了 microRNA-204 过表达的生物学表型。BIRC2 过表达促进了 GC 细胞的转移，挽救了 microRNA-204 对细胞迁移和 NF-κ b 信号通路的抑制作用。此外，较低的 microRNA-204 和较高的 BIRC2 表达水平与 GC 患者较差的预后相关。这些结果表明，幽门螺杆菌感染诱导的 microRNA-204 的表观遗传沉默增强了幽门螺杆菌诱导的胃炎和 GC 中的 NF-κ b 信号通路，可能为这些疾病提供新的干预靶点。幽门螺杆菌 (H. pylori) 感染对胃粘膜细胞 MicroRNA-204 有明显的抑制作用。它导致 BIRC2 表达水平和 BIRC2/TNF-a/NF-kB 信号通路活性增强，促进胃癌细胞的血管生成和转移。
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