Deciphering the role of nuclear and cytoplasmic IKKβ in skin cancer

Nonmelanoma skin cancers (NMSC) are the most common human malignancies. IKK beta 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 IKK beta protects against skin cancer, others indicate that it promotes NMSC. To resolve this controversy we have generated two models of transgenic mice expressing the IKK beta protein in the nucleus (N-IKK beta mice) or the cytoplasm (C-IKK beta 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 IKK beta promotes skin tumors are different depending on its subcellular localization; while IKK beta of cytoplasmic localization increases EGFR, MMP-9 and VEGF-A activities in tumors, nuclear IKK beta causes tumor progression through regulation of c-Myc, Maspin and Integrin-alpha 6 expression. Additionally, we have found that N-IKK beta skin tumors mimic the characteristics associated to aggressive human skin tumors with high risk to metastasize. Our results show that IKK beta has different non-overlapping roles in the nucleus or cytoplasm of keratinocytes, and provide new targets for intervention in human NMSC progression.