title: Enforced expression of nuclear factor kappa B in p53 deficient keratinocytes induces cell cycle, angiogenic potential and tumorigenesis.
abstract: Multiple genetic mutations with subsequent molecular events are required for progression of normal epithelial cells to cancer, with p53 mutations being a very common event in squamous carcinogenesis. Upregulation of nuclear factor kappa B (NF-κB) is an associated feature of malignancy, however studies have not examined purposeful overexpression of the NF-κB p65 subunit in in vitro models of oral carcinogenesis. Our objective is to demonstrate that NF-κB p65 transfection into p53 deficient Rhek keratinocytes produces carcinogenic progression. We constitutively over-expressed NF-κB p65 in Rhek keratinocytes, previously immortalized by SV 40 thus inactivating p53, and studied NF-κB dependent events. NF-κB p65 overexpression provided functional upregulation of NF-κB and produced cyclin D1-mediated proliferation and interleukin 8 transcription and secretion. Consequently, we demonstrated tumorigenesis in athymic mice with NF-κB p65 overexpressing cells. We conclude NF-κB p65 overexpression in p53 inactivated immortalized keratinocytes produces tumorigenesis, and that this single alteration in NF-κB expression on a p53 inactivated background is sufficient for squamous carcinogenesis features, thus providing evidence that p65 may act as a gain of function oncogene in this setting.
authors.affiliation: Department of Otolaryngology, University of Minnesota, Minneapolis, MN, USA. caic0001@umn.edu
authors.forename: Emiro E
authors.initials: EE
authors.lastname: Caicedo-Granados
authors.forename: Beverly R
authors.initials: BR
authors.lastname: Wuertz
authors.forename: Frank G
authors.initials: FG
authors.lastname: Ondrey
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1