title: Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model.
abstract: The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9-18 fold) of induction in the microarray data, and its early induction was observed in a 2h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Liu
authors.forename: Heng-Chien
authors.initials: HC
authors.lastname: Ho
authors.forename: Miau-Rong
authors.initials: MR
authors.lastname: Lee
authors.forename: Kuang-Chi
authors.initials: KC
authors.lastname: Lai
authors.forename: Chung-Min
authors.initials: CM
authors.lastname: Yeh
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Tin-Yun
authors.initials: TY
authors.lastname: Ho
authors.forename: Chien-Yun
authors.initials: CY
authors.lastname: Hsiang
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D002273:Carcinogens; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D018121:Receptors, Cytokine / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014062:Tongue Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D016207:Cytokines; D016328:NF-kappa B; D018121:Receptors, Cytokine; D015112:4-Nitroquinoline-1-oxide; D012313:RNA; D051546:Cyclooxygenase 2