Deciphering the role of nuclear and cytoplasmic IKKα in skin cancer
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Josefa P. Alameda1,2, Miriam Gaspar1, Ángel Ramírez1,2, Manuel Navarro1,2, Angustias Page1,2, Cristian Suárez-Cabrera1,2, M. Guadalupe Fernández3, Jose R. Mérida3, Jesús M. Paramio1,2, Rosa A. García-Fernández4, M. Jesús Fernández-Aceñero5, M. Llanos Casanova1,2
1Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28040 Madrid, Spain
2Molecular Oncology, Institute of Biomedical Investigation University Hospital “12 de Octubre”, 28041 Madrid, Spain
3Department of Human Anatomy and Embriology, Facultad de Medicina, UCM, 28040 Madrid, Spain
4Department of Animal Medicine and Surgery, Facultad de Veterinaria, UCM, 28040 Madrid, Spain
5Department of Pathology, Hospital Clínico San Carlos, 28040 Madrid, Spain
M. Llanos Casanova, email: [email protected]
Keywords: nuclear IKKα, cytoplasmic IKKα, skin cancer, Maspin, c-Myc
Received: November 06, 2015 Accepted: March 28, 2016 Published: April 18, 2016
Nonmelanoma skin cancers (NMSC) are the most common human malignancies. IKKα is an essential protein for skin development and is also involved in the genesis and progression of NMSC, through mechanisms not fully understood. While different studies show that IKKα protects against skin cancer, others indicate that it promotes NMSC. To resolve this controversy we have generated two models of transgenic mice expressing the IKKα protein in the nucleus (N-IKKα mice) or the cytoplasm (C-IKKα mice) of keratinocytes. Chemical skin carcinogenesis experiments show that tumors developed by both types of transgenic mice exhibit histological and molecular characteristics that make them more prone to progression and invasion than those developed by Control mice. However, the mechanisms through which IKKα promotes skin tumors are different depending on its subcellular localization; while IKKα of cytoplasmic localization increases EGFR, MMP-9 and VEGF-A activities in tumors, nuclear IKKα causes tumor progression through regulation of c-Myc, Maspin and Integrin-α6 expression. Additionally, we have found that N-IKKα skin tumors mimic the characteristics associated to aggressive human skin tumors with high risk to metastasize. Our results show that IKKα has different non-overlapping roles in the nucleus or cytoplasm of keratinocytes, and provide new targets for intervention in human NMSC progression.
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