title: Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling.
abstract: Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.|State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Z-M
authors.initials: ZM
authors.lastname: Shi
authors.affiliation: State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.affiliation: State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: C-F
authors.initials: CF
authors.lastname: Jiang
authors.affiliation: State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Ge
authors.affiliation: State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: D-M
authors.initials: DM
authors.lastname: Li
authors.affiliation: State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Wen
authors.affiliation: State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: H-R
authors.initials: HR
authors.lastname: Sun
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: M-H
authors.initials: MH
authors.lastname: Pan
authors.affiliation: Department of Pathology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Shu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Peiper
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: State Key Lab of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, China.|Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: B-H
authors.initials: BH
authors.lastname: Jiang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics*; D000071250:Snail Family Transcription Factors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D002945:Cisplatin