title: The increase of oncogenic miRNA expression in tongue carcinogenesis of a mouse model.
abstract: OBJECTIVE
  This study investigated the oncogenic miRNA level in the tissue and biofluids in the Nitroquinoline 1-Oxide (4NQO)-induced mouse tongue carcinogenesis model for potential diagnostic or therapeutic application.
  
  
  METHODS
  The histological examination, immunohistochemistry, in situ hybridization, quantitative PCR analysis and bioinformatic algorithms were performed to unravel the signaling activation and miRNA expression in female murine samples.
  
  
  RESULTS
  The increase of miR-21 and miR-31 staining, and EGFR activation paralleled the severity of 4NQO-induced epithelial pathogenesis in tongue epithelium. A progressive increase of miR-21, miR-31 and miR-146a in both saliva and plasma samples was also noted. miR-31 was the earliest emerging miRNA in the saliva. The increase of plasma miR-146a, miR-184 and miR-372 was detectable early in the induction, and it was particularly eminent at the most advanced lesion state. The combined analysis of the multiple oncogenic miRNAs in the plasma signified a potent discriminative capacity between normal and pathological states. As the blockage of EGFR or AKT activation drastically reverted the miR-21, miR-31 and miR-146a expression induced by 4NQO in human oral carcinoma cell lines, the results implicated a mechanistic linkage of the oncogenic miRNAs' induction through EGFR/AKT activation.
  
  
  CONCLUSIONS
  In this study, we show the dysregulation of oncogenic miRNAs in murine tongue tumorigenesis, which simulates human counterparts. Increased multiple miRNAs in the biofluids may be valuable non-invasive markers in detecting oral carcinogenesis at an early stage. This animal model may also be useful for developing liquid biopsies and prevention strategies against oral carcinoma by abrogating EGFR or oncogenic miRNAs.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Yu
authors.initials: YY
authors.lastname: Kao
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsi-Feng
authors.initials: HF
authors.lastname: Tu
authors.affiliation: Department of Dentistry, School 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, School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: ckcw@ym.edu.tw.
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, School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: sclin@ym.edu.tw.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Lin
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D017403:In Situ Hybridization; D051379:Mice; D035683:MicroRNAs / Q000097:blood / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D012463:Saliva / Q000737:chemistry
chemical_list: D035683:MicroRNAs; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt
keywords: Carcinogenesis; Marker; Plasma; Saliva; Tongue; miRNA