title: miR-124 represses the mesenchymal features and suppresses metastasis in Ewing sarcoma.
abstract: Metastasis is the most powerful predictor of poor outcome of Ewing sarcoma (ES). Thus, identification of new molecules involved in tumor metastasis is of crucial importance to reduce morbidity and mortality of this devastating disease. In this study, we found that miR-124, a highly conserved miRNA, was suppressed in ES tissues and might be associated with tumor metastasis through suppressing its mesenchymal features. Overexpression of miR-124 suppressed the invasion of ES cells in vitro and tumor metastasis in vivo, which might be achieved through suppressing its mesenchymal features, as overexpression of miR-124 could repress the mesenchymal genes expression, and inhibit cell differentiation to mesenchymal lineages in ES cells. However, when SLUG was experimentally restored in these cells, mesenchymal features including suppressed expression of mesenchymal genes and decreased invasive ability were observed. We also found that cyclin D2 (CCND2) was a novel target gene of miR-124, and was directly involved in miR-124-mediated suppressive effects on cell growth. Lastly, we found that treatment with 5-Aza-CdR restored the expression of miR-124, accompanied with suppressed cell proliferation, invasion and mesenchymal features of ES cells, which demonstrated that hypermethylation might be involved in the regulation of miR-124 expression. Collectively, our data suggest that hypermethylation-mediated suppression of miR-124 might be involved in the tumor initiation and metastasis through suppressing the mesenchymal features of ES cells.
authors.affiliation: Department of Gynecology and Obstetrics, the Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, PR China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Orthopedics, the Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, PR China.
authors.forename: Gaohai
authors.initials: G
authors.lastname: Shao
authors.affiliation: Department of Orthopedics, the Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, PR China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, the Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, PR China.
authors.forename: Fengchen
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Orthopedics, the Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics, the Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Orthopedics, the Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, PR China.
authors.forename: Zhongzu
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D016160:Retinoblastoma Protein; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors
keywords: Ewing sarcoma; SLUG; cyclin D2; mesenchymal features; miR-124