title: Epigenetic silencing of miR-490-3p reactivates the chromatin remodeler SMARCD1 to promote Helicobacter 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.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong. Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Zhangang
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong. Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. CUHK Shenzhen Research Institute, Shenzhen, China. wukakei@cuhk.edu.hk alfredcheng@cuhk.edu.hk.
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.affiliation: The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Maggie H
authors.initials: MH
authors.lastname: Wang
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Ka F
authors.initials: KF
authors.lastname: To
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong. Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Yangchao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Yang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: May S M
authors.initials: MS
authors.lastname: Li
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Shin
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Wei
authors.initials: W
authors.lastname: Kang
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Minxing
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Ruby L Y
authors.initials: RL
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Sunny H
authors.initials: SH
authors.lastname: Wong
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong. CUHK Shenzhen Research Institute, Shenzhen, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Matthew T V
authors.initials: MT
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Francis K L
authors.initials: FK
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong. Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong. wukakei@cuhk.edu.hk alfredcheng@cuhk.edu.hk.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong. Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Chi H
authors.initials: CH
authors.lastname: Cho
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016480:Helicobacter pylori / Q000472:pathogenicity; D006801:Humans; D008679:Metaplasia / Q000139:chemically induced; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C000589011:MIRN490 microRNA, mouse; D035683:MicroRNAs; C529549:Smarcd1 protein, mouse; D008770:Methylnitrosourea