Role of IKKα in skin squamous cell carcinomas

Abstract

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are two major types of skin cancer derived from keratinocytes. SCC is a more aggressive type of cancer than BCC in humans. One significant difference between SCC and BCC is that SCC development is generally associated with cell dedifferentiation and morphological changes. When SCC is converted to spindle cell carcinoma, the latest stage of cancer, the tumor cells change to a fibroblastic cell morphology (epithelial-to-mesenchymal transition) and lose their differentiation markers. Recently, several laboratories have reported altered IκB kinase α (IKKα) protein localization, downregulated IKKα, and IKKα gene deletions and mutations in human SCCs of the skin, lung, esophagus, and neck and head. In addition, IKKα reduction promotes chemical carcinogen- and ultraviolet B-induced skin carcinogenesis, and IKKα deletion in keratinocytes causes spontaneous skin SCCs, but not BCCs, in mice. Thus, IKKα emerges as a bona fide skin tumor suppressor. In this article, we will discuss the role of IKKα in skin SCC development.

Figure 1.. Keratinocytes isolated from Er (er/er) mice lack terminal differentiation marker filaggrin but express IKKα.

(A) Photos of WT, Er (er/er) and Ikkα^−/− newborns stained with toluidine blue. The result indicates that the impaired skin of er/er and Ikkα^−/− mice is not able to prevent water penetration. (B) Western blot compares expression of IKKβ, IKKγ and IKKα in the skin of Ikkα^−/−, WT and er/er newborn mice. (C) Western blot compares terminal differentiation marker filaggrin levels in cultured er/er and Ikkα^−/− keratinocytes. +IKKα: Overexpressed HA tagged IKKα (HA-IKKα) including WT, C-terminal 80-aminal acid deletion (C80); C: Control; KA: Kinase-inactive forms; WM: WT-keratinocyte culture medium (kDIF); WT: Wild-type. Reproduced from [24].

Figure 2.. Nuclear IKKα function in regulating keratinocyte proliferation and differentiation.

Arrows indicate positive directions and lines present the inhibitory effect. DNA symbols represent promoter regions of genes. EGF/TPA and TGF-β in bold represent exogenous stimuli for cells. ADAM: A disintegrin and metalloprotease; TPA: 12-0-tetradecanoylphorbol-13-acetate.