title: Role of miR-200c/miR-141 in the regulation of epithelial-mesenchymal transition and migration in head and neck squamous cell carcinoma.
abstract: Epithelial-mesenchymal-transition (EMT) is a critical step in tumor invasion and metastasis, while its fate is mainly defined by the balanced expression between the miR-200 family and ZEB transcription factors. In this study, we observed a reciprocal correlation between miR-200c/mir-141 and ZEB1, as well as between ZEB2 and E-cadherin expression in a panel of 13 head and neck squamous cell carcinoma (HNSCC) cell lines. We also confirmed that the enforced expression of miR-200c and miR-141 significantly reduced the migration capacity of HNSCC cells. Accordingly, the enforced expression of miR-200c and mir-141 resulted in a significant upregulation in E-cadherin expression, contrary to the significant downregulation in ZEB1 expression in 3 cell lines (UTSCC-24A, UTSCC-24B and UTSCC-6A cells). Another pair of cell lines, UTSCC-60A and UTSCC‑ 60B failed to show a significant change in the expression of E-cadherin or ZEB1/ZEB2 during the enforced expression of miR-200c/miR-141. To address the issue, we focused on the hypermethylation status of the ZEB1/2 promoters, which have both been shown to include wide CpG islands. We observed a marked upregulation in both ZEB1 and ZEB2 mRNA expression following treatment with a demethylating agent in both pairs of UTSCC cell lines. In conclusion, our findings confirm the existence of a reciprocal correlation between the mir-200 family and the ZEB family, and demonstrate the role of the miR-200 family in EMT, as well as in the migration and invasion ability of HNSCC cells. Furthermore, our data suggest that the promoter hypermethylation of ZEB1 and ZEB2 may play an essential role and may overshadow the effects of the miR-200 family in the regulation of EMT during carcinogenesis.
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Tamagawa
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Levent Bekir
authors.initials: LB
authors.lastname: Beder
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Muneki
authors.initials: M
authors.lastname: Hotomi
authors.affiliation: Department of Otolaryngology, Turgut Ozal University, Faculty of Medicine, Ankara, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Gunduz
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yata
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Central Hospital, Turku, Finland.
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamanaka
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D019175:DNA Methylation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D014157:Transcription Factors / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1