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

Abstract

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.