IKK beta-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent

摘要

IKKb (encoded by IKBKB) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-kappa B pathway. IKKb exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that IKBKB gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKb in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKb in the basal skin layer. IKKb overexpression resulted in a striking resistance to skin cancer development and an increased expression of several tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin tumor-protective role of IKKb is independent of p53, but dependent on the activity of the Ink4a/Arf locus. Interestingly, in the absence of p16 and p19, IKKb-increased expression favors the appearance of cutaneous spindle cell-like squamous cell carcinomas, which are highly aggressive tumors. These results reveal that IKKb activity prevents skin tumor development, and shed light on the complex nature of IKKb effects on cancer progression, as IKKb can both promote and prevent carcinogenesis depending on the cell type or molecular context.