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

Abstract

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