title: Epigenetic regulation of microRNA-10b and targeting of oncogenic MAPRE1 in gastric cancer.
abstract: MicroRNAs act as negative regulators of gene expression, and the altered expression of microRNAs by epigenetic mechanisms is strongly implicated in carcinogenesis. Here we report that the microRNA-10b gene (miR-10b) was silenced in gastric cancer cells by promoter methylation. In this study, using a methylation array and bisulfate pyrosequencing analysis, we found that miR-10b promoter CpGs were heavily methylated in gastric cancers. Clinicopathologic data showed that miR-10b methylation increased with patient age and occurred significantly more frequently in intestinal-type (28/44, 64%) than in diffuse-type (22/56, 39%) gastric cancers (P = 0.016). In addition, miR-10b methylation was also associated with an increase in expression of the oncogene that encodes microtubule-associated protein, RP/EB family, member 1 (MAPRE1; P = 0.004), which was identified as a potential miR-10b target. After 5-aza-2'-deoxycytidine treatment of gastric cancer cells, miR-10b methylation was significantly decreased, and expression of miR-10b and HOXD4, which is 1 kb downstream of miR-10b, was greatly restored. Moreover, decreased MAPRE1 expression coincided with increased miR-10b expression, suggesting that miR-10b targets MAPRE1 transcription. We also found that transfection with precursor miR-10b into gastric cancer cells dramatically decreased MAPRE1 mRNA and protein, resulting in a significant decrease in colony formation and cell growth rates. Thus, we show a tumor-suppressive role for miR-10b in gastric carcinogenesis. miR-10b methylation may be a useful molecular biomarker for assessing the risk of gastric cancer development, and modulation of miR-10b may represent a therapeutic approach for treating gastric cancer.
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
authors.forename: Kwoneel
authors.initials: K
authors.lastname: Kim
authors.forename: Han-Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Park
authors.forename: Mirang
authors.initials: M
authors.lastname: Kim
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Seung-Moo
authors.initials: SM
authors.lastname: Noh
authors.forename: Kyu-Sang
authors.initials: KS
authors.lastname: Song
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: C500985:MAPRE1 protein, human; C547183:MIRN10 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins