title: MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity.
abstract: miR-211 expression in human oral squamous cell carcinoma (OSCC) has been implicated in poor patient survival. To investigate the oncogenic roles of miR-211, we generated K14-EGFP-miR-211 transgenic mice tagged with GFP. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that family with sequence similarity 213, member A (FAM213A), a peroxiredoxin-like antioxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population, and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment downregulated TCF12 and upregulated FAM213A by modulating miR-211 both in vitro and in vivo Overall, our findings develop a mouse model that recapitulates the molecular and histopathologic alterations of human OSCC pathogenesis and highlight a new miRNA-mediated oncogenic mechanism. Cancer Res; 76(16); 4872-86. ©2016 AACR.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, National Yang-Ming University, Taipei, Taiwan. Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Dentistry, National Yang-Ming University, Taipei, Taiwan. Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shou-Yen
authors.initials: SY
authors.lastname: Kao
authors.affiliation: Department of Dentistry, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, MacKay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chung-Ji
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, National Yang-Ming University, Taipei, Taiwan. Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. ckcw@ym.edu.tw sclin@ym.edu.tw.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, National Yang-Ming University, Taipei, Taiwan. Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. ckcw@ym.edu.tw sclin@ym.edu.tw.
authors.forename: Kuo-Wei
authors.initials: KW
authors.lastname: Chang
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics*; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D000077195:Squamous Cell Carcinoma of Head and Neck; D046888:Tissue Array Analysis
chemical_list: D015112:4-Nitroquinoline-1-oxide; D051792:Basic Helix-Loop-Helix Proteins; D002273:Carcinogens; D035683:MicroRNAs; C577982:Mirn211 microRNA, mouse; C489532:Tcf12 protein, mouse