Reduction in IκB kinase α expression promotes the development of skin papillomas and carcinomas

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