title: K14-EGFP-miR-31 transgenic mice have high susceptibility to chemical-induced squamous cell tumorigenesis that is associating with Ku80 repression.
abstract: Squamous cell carcinoma (SCC) occurring in the head and neck region and the esophagus causes tremendous cancer mortality around the world. miR-31 is among the most eminently upregulated MicroRNAs in SCC, when it occurs in the head and neck region and the esophagus. We established miR-31 transgenic mouse lines, in which miR-31 is under the control of the K14 promoter. 4-nitroquinoline 1-oxide (4NQO) is a mutagen that causes double strand breaks. The transgenic mice exhibited a higher potential for tumor induction than wild-type (Wt) mice of the tongue and esophagus after 4NQO treatment. After 4NQO treatment or irradiation, p-γH2AX expression in squamous epithelium of transgenic mice was increased more than in Wt mice. Exogenous expression of miR-31 was also found to be associated with the higher p-γH2AX expression induced by 4NQO in human oral SCC (OSCC) cell lines. The repair genes PARP1 and Ku80 were validated as new targets of miR-31 in human OSCC cell lines, and were found to be downregulated in the squamous epithelium of the tongue in transgenic mice. However, only the downregulation of Ku80 was essential for maintaining the high level of p-γH2AX induced by 4NQO in OSCC cells. Inverse expression profiles for miR-31 and Ku80 were noted in human OSCC tissue. Our study identifies the high sensitivity of K14-EGFP-miR-31 transgenic mice to chemical carcinogen-induced squamous cell tumorigenesis and shows that this seems to be associated with the downregulation of Ku80 and an impairment of repair activity in squamous cells, which are mediated by miR-31.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ssu-Hsueh
authors.initials: SH
authors.lastname: Tseng
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yang
authors.forename: En-Hao
authors.initials: EH
authors.lastname: Yu
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: Yong-Syu
authors.initials: YS
authors.lastname: Lee
authors.forename: Chung-Ji
authors.initials: CJ
authors.lastname: Liu
authors.forename: Kuo-Wei
authors.initials: KW
authors.lastname: Chang
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Lin
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D034961:Antigens, Nuclear / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D004938:Esophageal Neoplasms / Q000139:chemically induced; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006657:Histones / Q000032:analysis; D006801:Humans; D000072200:Ku Autoantigen; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D009062:Mouth Neoplasms / Q000139:chemically induced*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C539917:Mirn31 microRNA, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D015112:4-Nitroquinoline-1-oxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen
keywords: Ku80; MicroRNA; PARP1; miR-31; mouth; transgenic mouse