title: Regulation of UHRF1 by miR-146a/b modulates gastric cancer invasion and metastasis.
abstract: Epigenetic changes play significant roles in the development of cancer. UHRF1, as an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene silencing in several cancers. However, the role and underlying mechanism of UHRF1 in gastric cancer (GC) progression remain largely unknown. In this study, we investigated the expression and function of UHRF1 in GC metastasis and explored its upstream regulatory mechanisms at the microRNA level. UHRF1 was overexpressed in GC tissues, especially in metastatic ones, and a high level of UHRF1 expression predicted poor survival. The down-regulation of UHRF1 suppressed GC invasion and metastasis in vitro and in vivo. We identified and verified miR-146a and miR-146b as direct upstream regulators of UHRF1. Furthermore, the restoration of miR-146a/b dramatically reduced the expression of UHRF1 through the direct targeting of its 3'-UTR, and this effect in turn reactivated the slit homologue 3 (Slit3), cadherin 4 (CDH4), and runt-related transcription factor 3 (RUNX3) genes via promoter demethylation. Finally, analyses of miR-146a/b and UHRF1 levels in human GC tissues revealed that miR-146a/b correlated inversely with UHRF1 expression. These findings describe a new mechanism for the regulation of UHRF1 and aberrant DNA hypermethylation in GC. The newly identified miR-146a/b/UHRF1 axis provides insight into the GC metastasis process, and targeting this novel axis represents a therapeutic approach to blocking GC metastasis.
authors: 3Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, West Changle Road, Xi'an 710032, China. K. W., kaicwu@fmmu.edu.cn.
authors: Lin
authors: L
authors: Zhou
authors: Xiaodi
authors: X
authors: Zhao
authors: Yanan
authors: Y
authors: Han
authors: Yuanyuan
authors: Y
authors: Lu
authors: Yulong
authors: Y
authors: Shang
authors: Changhao
authors: C
authors: Liu
authors: Ting
authors: T
authors: Li
authors: Zhian
authors: Z
authors: Jin
authors: Daiming
authors: D
authors: Fan
authors: Kaichun
authors: K
authors: Wu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases
chemical_list: D020413:3' Untranslated Regions; D022762:CCAAT-Enhancer-Binding Proteins; D015820:Cadherins; D050677:Core Binding Factor Alpha 3 Subunit; C542542:MIRN146 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C083970:R-cadherin; C493729:Runx3 protein, human; C498990:SLIT3 protein, human; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: DNA methylation; metastasis