Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas.

We reported recently a marked reduction in IkappaB kinase alpha (IKKalpha) expression in a large proportion of human poorly differentiated squamous cell carcinomas (SCC) and the occurrence of Ikkalpha mutations in human SCCs. In addition, overexpression of IKKalpha in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKKalpha expression promotes skin tumor development is currently unknown. Here, we assessed the susceptibility of Ikkalpha hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikkalpha+/- mice developed 2 times more papillomas and 11 times more carcinomas than did Ikkalpha+/+ mice. The tumors were larger in Ikkalpha+/- than in Ikkalpha+/+ mice, but tumor latency was shorter in Ikkalpha+/- than in Ikkalpha+/+ mice. Some of the Ikkalpha+/- papillomas and most Ikkalpha+/- carcinomas lost the remaining Ikkalpha wild-type allele. Somatic Ikkalpha 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 Ikkalpha+/- than in Ikkalpha+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKKalpha 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 IKKalpha expression promotes the development of papillomas and carcinomas and that the integrity of the Ikkalpha gene is required for suppressing skin carcinogenesis.

A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas.

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