Deciphering the role of nuclear and cytoplasmic IKKα in skin cancer

// Josefa P. Alameda 1, 2 , Miriam Gaspar 1 , Angel Ramirez 1, 2 , Manuel Navarro 1, 2 , Angustias Page 1, 2 , Cristian Suarez-Cabrera 1, 2 , M. Guadalupe Fernandez 3 , Jose R. Merida 3 , Jesus M. Paramio 1, 2 , Rosa A. Garcia-Fernandez 4 , M. Jesus Fernandez-Acenero 5 , M. Llanos Casanova 1, 2 1 Molecular Oncology Unit, Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT), 28040 Madrid, Spain 2 Molecular Oncology, Institute of Biomedical Investigation University Hospital “12 de Octubre”, 28041 Madrid, Spain 3 Department of Human Anatomy and Embriology, Facultad de Medicina, UCM, 28040 Madrid, Spain 4 Department of Animal Medicine and Surgery, Facultad de Veterinaria, UCM, 28040 Madrid, Spain 5 Department of Pathology, Hospital Clinico San Carlos, 28040 Madrid, Spain Correspondence to: M. Llanos Casanova, email: llanos.casanova@ciemat.es Keywords: nuclear IKKα, cytoplasmic IKKα, skin cancer, Maspin, c-Myc Received: November 06, 2015      Accepted: March 28, 2016      Published: April 18, 2016 SUMMARY 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.