Reduction of IKK alpha Expression Promotes Chronic Ultraviolet B Exposure-Induced Skin Inflammation and Carcinogenesis

Ultraviolet B light (UVB) is a common cause of human skin cancer. UVB irradiation induces mutations in the tumor suppressor p53 gene as well as chronic inflammation, which are both essential for UVB carcinogenesis. Inhibitor of nuclear factor kappa B kinase-alpha (IKK alpha) plays an important role in maintaining skin homeostasis, and expression of IKK alpha was found to be down-regulated in human and murine skin squamous cell carcinomas. However, the role of IKK alpha in UVB skin carcinogenesis has not been investigated. Thus, here we performed UVB carcinogenesis experiments on Ikk alpha(+/+) and Ikk alpha(+/-) mice. Ikk alpha(+/-) mice were found to develop a twofold greater number of skin tumors than Ikk alpha(+/+) mice after chronic UVB irradiation. In addition, tumor latency was significantly shorter and tumors were bigger in IKK alpha(+/-) than in Ikk alpha(+/+) mice. At an early stage of carcinogenesis, an increase in UVB-induced p53 mutations as well as macrophage recruitment and mitogenic activity, and a decrease in UVB-induced apoptosis, were detected in Ikk alpha(+/-) compared with those in Ikk alpha(+/+) skin. Also, reduction of IKK alpha levels in keratinocytes up-regulated the expression of monocyte chemoattractant protein-1 (MCP-1/CCL2), TNF alpha, IL-1, and IL-6, and elevated macrophage migration, which might promote macrophage recruitment and inflammation. Therefore, these findings suggest that reduction of IKK alpha expression orchestrates UVB carcinogen, accelerating tumorigenesis. (Am J Pathol 2010, 176:2500-2508; DOI: 10.2353/ajpath.2010.091041)

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