Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2017; 8:53887.

IKKα regulates the stratification and differentiation of the epidermis: implications for skin cancer development

Josefa P. Alameda, Manuel Navarro, Ángel Ramírez, Angustias Page, Cristian Suárez-Cabrera, Rodolfo Moreno-Maldonado, Jesús M. Paramio, María del Carmen Fariña, Marcela Del Río, María Jesús Fernández-Aceñero, Ana Bravo and María de los Llanos Casanova _

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Oncotarget. 2016; 7:76779-76792. https://doi.org/10.18632/oncotarget.12527

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Abstract

Josefa P. Alameda1,2, Manuel Navarro1,2, Ángel Ramírez1,2, Angustias Page1,2, Cristian Suárez-Cabrera1,2, Rodolfo Moreno-Maldonado3, Jesús M. Paramio1,2, María del Carmen Fariña4, Marcela Del Río5,6,7, María Jesús Fernández-Aceñero8, Ana Bravo9, María de los Llanos Casanova1,2

1Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

2Molecular Oncology, Institute of Biomedical Investigation University Hospital “12 de Octubre”, Madrid, Spain

3Present address: SILO España, Madrid, Spain

4Department of Dermatology, Fundación Jiménez Díaz, Madrid, Spain

5Epithelial Biomedicine Division, CIEMAT-CIBERER (U714), Madrid, Spain

6Department of Bioengineering, Carlos III University (UC3M), Leganés, Madrid, Spain

7Cátedra Fundación Jiménez Díaz (IIS-FJD) of Regenerative Medicine and Tissue Bioengineer, Madrid, Spain

8Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain

9Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Santiago de Compostela, Lugo, Spain

Correspondence to:

M. Llanos Casanova, email: [email protected]

Keywords: IKKα, keratinocyte differentiation, MMP9, skin, skin cancer

Received: July 29, 2016     Accepted: September 29, 2016     Published: October 08, 2016

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.


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