Epigenetic silencing of microRNA-204 by Helicobacter pylori augments the NF-κB signaling pathway in gastric cancer development and progression.

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.

• Authors: Peizhan Chen, He Guo, Xuming Wu, Jingquan Li, Xiaohua Duan, Qian Ba, Hui Wang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 41 Issue 4 Pg. 430-441 (06 17 2020) ISSN: 1460-2180 [Electronic] England
• PMID: 31873718 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Biomarkers, Tumor
• Inhibitor of Apoptosis Proteins
• MIRN204 microRNA, human
• MicroRNAs
• NF-kappa B
• BIRC2 protein, human
• Ubiquitin-Protein Ligases

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Disease Progression
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Helicobacter Infections (complications, microbiology)
• Helicobacter pylori (isolation & purification)
• Humans
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• MicroRNAs (genetics)
• NF-kappa B (genetics, metabolism)
• Prognosis
• Stomach Neoplasms (genetics, metabolism, microbiology, pathology)
• Survival Rate
• Tumor Cells, Cultured
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Xenograft Model Antitumor Assays