Yinling Hu

We reported recently a marked reduction in IκB kinase α (IKKα) expression in a large proportion of human poorly differentiated squamous cell carcinomas (SCC) and the occurrence of Ikkα mutations in human SCCs. In addition, overexpression of IKKα in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKKα expression promotes skin tumor development is currently unknown. Here, we assessed the susceptibility of Ikkα hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikkα^+/− mice developed 2 times more papillomas and 11 times more carcinomas than did Ikkα^+/+ mice. The tumors were larger in Ikkα^+/− than in Ikkα^+/+ mice, but tumor latency was shorter in Ikkα^+/− than in Ikkα^+/+ mice. Some of the Ikkα^+/− papillomas and most Ikkα^+/− carcinomas lost the remaining Ikkα wild-type allele. Somatic Ikkα mutations were detected in carcinomas and papillomas. The chemical carcinogen-induced H-Ras mutations were detected in all the tumors. The phorbol ester tumor promoter induced higher mitogenic and angiogenic activities in Ikkα^+/− than in Ikkα^+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKKα expression provided a selective growth advantage, which cooperated with H-Ras mutations to promote papilloma formation. Furthermore, excessive extracellular signal-regulated kinase and IKK kinase activities were observed in carcinomas compared with those in papillomas. Thus, the combined mitogenic, angiogenic, and IKK activities might contribute to malignant conversion. Our findings provide evidence that a reduction in IKKα expression promotes the development of papillomas and carcinomas and that the integrity of the Ikkα gene is required for suppressing skin carcinogenesis. [Cancer Res 2007;67(19):9158–68]

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 Ikk α mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKKα expression in poorly differentiated human SCCs and identified Ikk α mutations in exon 15 of Ikk α 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.