title: Deregulation between miR-29b/c and DNMT3A is associated with epigenetic silencing of the CDH1 gene, affecting cell migration and invasion in gastric cancer.
abstract: The de-regulation of the miR-29 family and DNA methyltransferase 3A (DNMT3A) is associated with gastric cancer (GC). While increasing evidence indicates miR-29b/c could regulate DNA methylation by targeting DNMT3A, it is currently unknown if epigenetic silencing of miR-29b/c via promoter hypermethylation in GC is caused by abnormal expression of DNMT3A. Thus, we aimed to evaluate whether cross-talk regulation exists between miR-29b/c and DNMT3A and whether it is associated with a malignant phenotype in GC. First, wound healing and Transwell assays revealed that miR-29b/c suppresses tumor metastasis in GC. A luciferase reporter assay demonstrated that DNMT3A is a direct target of miR-29b/c. We used bisulfite genomic sequencing to analyze the DNA methylation status of miR-29b/c. The percentage of methylated CpGs was significantly decreased in DNMT3A-depleted cells compared to the controls. Furthermore, the involvement of DNMT3A in promoting GC cell migration was associated with the promoter methylation-mediated repression of CDH1. In 50 paired clinical GC tissue specimens, decreased miR-29b/c was significantly correlated with the degree of differentiation and invasion of the cells and was negatively correlated with DNMT3A expression. Together, our preliminary results suggest that the following process may be involved in GC tumorigenesis. miR-29b/c suppresses the downstream gene DNMT3A, and in turn, miR-29b/c is suppressed by DNMT3A in a DNA methylation-dependent manner. The de-regulation of both of miR-29b/c and DNMT3A leads to the epigenetic silencing of CDH1 and contributes to the metastasis phenotype in GC. This finding reveals that DNA methylation-associated silencing of miR-29b/c is critical for GC development and thus may be a therapeutic target.
authors: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
authors: He
authors: H
authors: Cui
authors: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
authors: Ling
authors: L
authors: Wang
authors: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
authors: Pihai
authors: P
authors: Gong
authors: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
authors: Chengcheng
authors: C
authors: Zhao
authors: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
authors: Shaodan
authors: S
authors: Zhang
authors: The 3rd Affiliated Hospital of Harbin Medical University (Harbin Medical University Cancer Hospital), Harbin, 150081, China.
authors: Kun
authors: K
authors: Zhang
authors: The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, 210000, China.
authors: Rongping
authors: R
authors: Zhou
authors: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
authors: Zhujiang
authors: Z
authors: Zhao
authors: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
authors: Hong
authors: H
authors: Fan
mesh_terms: D015703:Antigens, CD; D001681:Biological Assay; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D014945:Wound Healing
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000717967:DNMT3A protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D008156:Luciferases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A