title: IKKα regulates the stratification and differentiation of the epidermis: implications for skin cancer development.
abstract: IKKα plays a mandatory role in keratinocyte differentiation and exerts an important task in non-melanoma skin cancer development. However, it is not fully understood how IKKα exerts these functions. To analyze in detail the role of IKKα in epidermal stratification and differentiation, we have generated tridimensional (3D) cultures of human HaCaT keratinocytes and fibroblasts in fibrin gels, obtaining human skin equivalents that comprise an epidermal and a dermal compartments that resembles both the structure and differentiation of normal human skin. We have found that IKKα expression must be strictly regulated in epidermis, as alterations in its levels lead to histological defects and promote the development of malignant features. Specifically, we have found that the augmented expression of IKKα results in increased proliferation and clonogenicity of human keratinocytes, and leads to an accelerated and altered differentiation, augmented ability of invasive growth, induction of the expression of oncogenic proteins (Podoplanin, Snail, Cyclin D1) and increased extracellular matrix proteolytic activity. All these characteristics make keratinocytes overexpressing IKKα to be at a higher risk of developing skin cancer. Comparison of genetic profile obtained by analysis of microarrays of RNA of skin equivalents from both genotypes supports the above described findings.
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital "12 de Octubre", Madrid, Spain.
authors.forename: Josefa P
authors.initials: JP
authors.lastname: Alameda
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital "12 de Octubre", Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital "12 de Octubre", Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Ramírez
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital "12 de Octubre", Madrid, Spain.
authors.forename: Angustias
authors.initials: A
authors.lastname: Page
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital "12 de Octubre", Madrid, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Suárez-Cabrera
authors.affiliation: Present address: SILO España, Madrid, Spain.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Moreno-Maldonado
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital "12 de Octubre", Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
authors.affiliation: Department of Dermatology, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: María
authors.initials: MR
authors.lastname: del Carmen Fariña
authors.affiliation: Epithelial Biomedicine Division, CIEMAT-CIBERER (U714), Madrid, Spain.|Department of Bioengineering, Carlos III University (UC3M), Leganés, Madrid, Spain.|Cátedra Fundación Jiménez Díaz (IIS-FJD) of Regenerative Medicine and Tissue Bioengineer, Madrid, Spain.
authors.forename: Marcela
authors.initials: M
authors.lastname: Del Río
authors.affiliation: Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Fernández-Aceñero
authors.affiliation: Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Santiago de Compostela, Lugo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Bravo
authors.affiliation: Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Molecular Oncology, Institute of Biomedical Investigation University Hospital "12 de Octubre", Madrid, Spain.
authors.forename: María
authors.initials: MR
authors.lastname: de Los Llanos Casanova
keywords: IKKα; MMP9; keratinocyte differentiation; skin; skin cancer