title: Increased IKKα expression in the basal layer of the epidermis of transgenic mice enhances the malignant potential of skin tumors.
abstract: Non-melanoma skin cancer is the most frequent type of cancer in humans. In this study we demonstrate that elevated IKKα expression in murine epidermis increases the malignancy potential of skin tumors. We describe the generation of transgenic mice overexpressing IKKα in the basal, proliferative layer of the epidermis and in the outer root sheath of hair follicles. The epidermis of K5-IKKα transgenic animals shows several alterations such as hyperproliferation, mislocalized expression of integrin-α6 and downregulation of the tumor suppressor maspin. Treatment of the back skin of mice with the mitogenic agent 12-O-tetradecanoylphorbol-13-acetate causes in transgenic mice the appearance of different preneoplastic changes such as epidermal atypia with loss of cell polarity and altered epidermal tissue architecture, while in wild type littermates this treatment only leads to the development of benign epidermal hyperplasia. Moreover, in skin carcinogenesis assays, transgenic mice carrying active Ha-ras (K5-IKKα-Tg.AC mice) develop invasive tumors, instead of the benign papillomas arising in wild type-Tg-AC mice also bearing an active Ha-ras. Therefore we provide evidence for a tumor promoter role of IKKα in skin cancer, similarly to what occurs in other neoplasias, including hepatocarcinomas and breast, prostate and colorectal cancer. The altered expression of cyclin D1, maspin and integrin-α6 in skin of transgenic mice provides, at least in part, the molecular bases for the increased malignant potential found in the K5-IKKα skin tumors.
authors.affiliation: Division of Epithelial Biomedicine, CIEMAT, Madrid, Spain.
authors.forename: Josefa P
authors.initials: JP
authors.lastname: Alameda
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Moreno-Maldonado
authors.forename: M Jesús
authors.initials: MJ
authors.lastname: Fernández-Aceñero
authors.forename: Manuel
authors.initials: M
authors.lastname: Navarro
authors.forename: Angustias
authors.initials: A
authors.lastname: Page
authors.forename: José L
authors.initials: JL
authors.lastname: Jorcano
authors.forename: Ana
authors.initials: A
authors.lastname: Bravo
authors.forename: Ángel
authors.initials: Á
authors.lastname: Ramírez
authors.forename: M Llanos
authors.initials: ML
authors.lastname: Casanova
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D039503:Integrin alpha6 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011817:Rabbits; D015843:Serpins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000201:enzymology / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D039503:Integrin alpha6; D016328:NF-kappa B; C085344:SERPIN-B5; D015843:Serpins; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D013755:Tetradecanoylphorbol Acetate