The skin functions as a barrier between the organism and the surrounding environment. Direct exposure to external stimuli and the accumulation of genetic mutations may lead to abnormal cell growth, irreversible tissue damage and potentially favor skin malignancy. Skin homeostasis is coordinated by an intricate signaling network, and its dysregulation has been implicated in the development of skin cancers. Wnt signaling is one such regulatory pathway orchestrating skin development, homeostasis, and stem cell activation. Aberrant regulation of Wnt signaling cascades not only gives rise to tumor initiation, progression and invasion, but also maintains cancer stem cells which contribute to tumor recurrence. In this review, we summarize recent studies highlighting functional evidence of Wnt-related oncology in keratinocyte carcinomas, as well as discussing preclinical and clinical approaches that target oncogenic Wnt signaling to treat cancers. Our review provides valuable insight into the significance of Wnt signaling for future interventions against keratinocyte carcinomas.
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