title: Grainyhead-like 2 regulates epithelial plasticity and stemness in oral cancer cells.
abstract: Grainyhead-like 2 (GRHL2) is one of the three mammalian homologues of Drosophila Grainyhead involved in epithelial morphogenesis. We recently showed that GRHL2 also controls normal epithelial cell proliferation and differentiation. In this study, we investigated the role of GRHL2 in oral carcinogenesis and the underlying mechanism. GRHL2 expression was elevated in cells and tissues of oral squamous cell carcinomas (OSCCs) compared with normal counterparts. Knockdown of GRHL2 resulted in the loss of in vivo tumorigenicity, cancer stemness and epithelial phenotype of oral cancer cells. GRHL2 loss also inhibited oral cancer cell proliferation and colony formation. GRHL2 regulated the expression of miR-200 family and Octamer-binding transcription factor 4 (Oct-4) genes through direct promoter DNA binding. Overexpression of miR-200 genes in the oral cancer cells depleted of GRHL2 partially restored the epithelial phenotype, proliferative rate and cancer stemness, indicating that miR-200 genes in part mediate the functional effects of GRHL2. Taken together, this study demonstrates a novel connection between GRHL2 and miR-200, and supports protumorigenic effect of GRHL2 on OSCCs.
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA, School of Dentistry, Kyung Hee University, Seoul 130-872, Korea.
authors.forename: Jin Kyu
authors.initials: JK
authors.lastname: Yi
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Shimane
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Shebli
authors.initials: S
authors.lastname: Mehrazarin
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA, Jonsson Comprehensive Cancer Center and.
authors.forename: Ki-Hyuk
authors.initials: KH
authors.lastname: Shin
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA, Jonsson Comprehensive Cancer Center and.
authors.forename: Reuben H
authors.initials: RH
authors.lastname: Kim
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA, Jonsson Comprehensive Cancer Center and David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA, Jonsson Comprehensive Cancer Center and mkang@dentistry.ucla.edu.
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; D014157:Transcription Factors