title: EGF up-regulates miR-31 through the C/EBPβ signal cascade in oral carcinoma.
abstract: Oral squamous cell carcinoma (OSCC) is one of the most prevalent carcinomas worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression and modulate physiological or pathological processes including OSCC carcinogenesis. miR-31 has been found to be up-regulated in OSCC and to act as an oncogenic miRNA. However, the molecular mechanism underlying miR-31 up-regulation in OSCC is still obscure. The activation of epidermal growth factor receptor (EGFR) signaling axis plays key roles in driving oral carcinogenesis. Our screening identified that there is up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment. Subsequent analysis showed that EGF treatment led to AKT activation, which then resulted in miR-31 up-regulation. Moreover, EGF treatment and the AKT activation induced by exogenous expression up-regulated C/EBPβ expression. The miR-31 up-regulation induced by EGF was abrogated by AKT inhibition or by the knockdown of C/EBPβ expression. In OSCC cell subclones stably overexpressing the functional isoform of C/EBPβ, miR-31 expression was up-regulated. Curcumin is a natural ingredient exhibiting anti-cancer potential. It was found that curcumin attenuated AKT activation and the up-regulation of C/EBPβ and miR-31 caused by EGF stimulation in OSCC cells. Lastly, concordance across the expression of EGFR, the expression of C/EBPβ and the expression of miR-31 in OSCC tissues was found. This study describes a novel scenario where the up-regulation of miR-31 expression in OSCC is, at least in part, a consequence of EGFR oncogenic activation. Although the AKT activation and C/EBPβ expression after EGF treatment might not be directly linked, both events are the crucial mediators underlying miR-31 up-regulation in the EGFR signaling axis.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Lu
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: 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 Dentistry, National Yang-Ming University Hospital, Yi-Lan, Taiwan.
authors.forename: Hsi-Feng
authors.initials: HF
authors.lastname: Tu
authors.affiliation: Department of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Cheng-Hsien
authors.initials: CH
authors.lastname: Wu
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: Kuo-Wei
authors.initials: KW
authors.lastname: Chang
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: Shu-Chun
authors.initials: SC
authors.lastname: Lin
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin