title: MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines.
abstract: Down-regulation of miR-138 (microRNA-138) has been frequently observed in various cancers, including HNSCC (head and neck squamous cell carcinoma). Our previous studies suggest that down-regulation of miR-138 is associated with mesenchymal-like cell morphology and enhanced cell migration and invasion. In the present study, we demonstrated that these miR-138-induced changes were accompanied by marked reduction in E-cad (E-cadherin) expression and enhanced Vim (vimentin) expression, characteristics of EMT (epithelial-mesenchymal transition). On the basis of a combined experimental and bioinformatics analysis, we identified a number of miR-138 target genes that are associated with EMT, including VIM, ZEB2 (zinc finger E-box-binding homeobox 2) and EZH2 (enhancer of zeste homologue 2). Direct targeting of miR-138 to specific sequences located in the mRNAs of the VIM, ZEB2 and EZH2 genes was confirmed using luciferase reporter gene assays. Our functional analyses (knock-in and knock-down) demonstrated that miR-138 regulates the EMT via three distinct pathways: (i) direct targeting of VIM mRNA and controlling the expression of VIM at a post-transcriptional level, (ii) targeting the transcriptional repressors (ZEB2) which in turn regulating the transcription activity of the E-cad gene, and (iii) targeting the epigenetic regulator EZH2 which in turn modulates its gene silencing effects on the downstream genes including E-cad. These results, together with our previously observed miR-138 effects on cell migration and invasion through targeting RhoC (Rho-related GTP-binding protein C) and ROCK2 (Rho-associated, coiled-coil-containing protein kinase 2) concurrently, suggest that miR-138 is a multi-functional molecular regulator and plays major roles in EMT and in HNSCC progression.
authors.affiliation: Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Liu
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Zujian
authors.initials: Z
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Antonia
authors.initials: A
authors.lastname: Kolokythas
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhou
mesh_terms: D015820:Cadherins / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D014746:Vimentin / Q000235:genetics
chemical_list: D015820:Cadherins; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D014746:Vimentin