A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas

IKK (IKB kinase) a is essential for embryonic skin development in mice. Mice deficient in IKK alpha display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKK alpha in human skin diseases remains largely unknown. To shed light on the role of IKK alpha in human skin diseases, we examined IKK alpha expression and Ikk alpha mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKK alpha expression in poorly differentiated human SCCs and identified Ikk alpha mutations in exon 15 of Ikk alpha in eight of nine human SCCs, implying that lKK alpha is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKK alpha in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKK alpha transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKK alpha in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases.