Epigenetic silencing of miR-490-3p reactivates the chromatin remodeler SMARCD1 to promote Helicobacter pylori-induced gastric carcinogenesis

Cancer Res. 2015 Feb 15;75(4):754-65. doi: 10.1158/0008-5472.CAN-14-1301. Epub 2014 Dec 12.


Chromatin remodeling has emerged as a hallmark of gastric cancer, but the regulation of chromatin regulators other than genetic change is unknown. Helicobacter pylori causes epigenetic dysregulation to promote gastric carcinogenesis, but the roles and functions of microRNAs (miRNA) in this multistage cascade are not fully explored. In this study, miRNA expression in preneoplastic and neoplastic lesions in murine stomachs induced by H. pylori and N-methyl-N-nitrosourea (MNU) was profiled by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Significant downregulation of miR-490-3p was confirmed in human gastric cancer tissues in which its regulatory region was found to be hypermethylated. miR-490-3p exerted growth- and metastasis-suppressive effects on gastric cancer cells through directly targeting SMARCD1, a SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex subunit. Knockdown of SMARCD1 significantly attenuated the protumorigenic effects of miR-490-3p inhibitor, whereas enforced expression of SMARCD1 promoted in vitro and in vivo oncogenic phenotypes of gastric cancer cells. SMARCD1 was markedly upregulated in gastric cancer in which its high expression was associated with shortened patients' survival independent of TNM staging. In conclusion, hypermethylation-mediated silencing of miR-490-3p reactivates SMARCD1 to confer malignant phenotypes, mechanistically linking H. pylori, chromatin remodeling, and gastric carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemically induced
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Animals
  • Carcinogenesis*
  • Cell Line, Tumor
  • Chromatin Assembly and Disassembly / genetics
  • Chromosomal Proteins, Non-Histone
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Helicobacter pylori / pathogenicity
  • Humans
  • Metaplasia / chemically induced
  • Methylnitrosourea / toxicity
  • Mice
  • MicroRNAs / genetics*
  • Stomach Neoplasms / chemically induced
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology


  • Chromosomal Proteins, Non-Histone
  • MIRN490 microRNA, mouse
  • MicroRNAs
  • Smarcd1 protein, mouse
  • Methylnitrosourea