Epigenetic Silencing of miR-490-3p Reactivates the Chromatin Remodeler SMARCD1 to PromoteHelicobacter pylori–Induced Gastric Carcinogenesis

Abstract

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. Cancer Res; 75(4); 754-65. Ó2014 AACR.

High-throughput sequencing of pituitary and hypothalamic microRNA transcriptome associated with high rate of egg production

“…For example, miR-138 [75–77], miR-29a [78–81], miR-490-3p [82, 83], miR-9-3p [84–86], and miR-135 [87–90] have pivotal roles in tumorigenesis and tumor progression by acting as tumor suppressors. miR-138 modulates the DNA damage response by repressing histone H2AX expression [91].…”

Unveiling the Impact of the Genomic Architecture on the Evolution of Vertebrate microRNAs

“…Although miR-490 is annotated as intergenic in chicken, predicted transcripts with an intron overlapping miR-490 are annotated. Expression analyses reveal a strongly conserved pattern among human, rhesus macaque, mouse, and chicken; indicating concomitant expression of miR-490 and CHRM2 (Shen et al, 2015) with highest abundance in heart ( Figure 1A ). The host gene is a muscarinic cholinergic receptor involved in acetylcholine-mediated cardiac chronotropic (heart rate) and inotropic (strength of muscle contraction) effects (Brodde and Michel, 1999), and it has been associated with cardiomyopathy (Zhang et al, 2008).…”

Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

“…The metabolic miRNAs, including miR-33, miR-103, miR-107 and miR-143, play pivotal roles in controlling the metabolism and homeostasis of insulin, glucose, cholesterol and lipid in vivo [25,26,27]. It has become clear that alterations in the expression of miRNAs contribute to the pathogenesis of most human cancers [28,29,30]. A number of differentially-expressed miRNAs that function in hepatic cholesterol and fatty acid homeostasis have been shown to contribute to the pathogenesis of HCC in NAFLD [15].…”