Functions of IKK alpha in Skin Homeostasis and Skin Tumorigenesis

Division Of Basic Sciences - Nci

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Abstract

Pattern-recognition receptors play a critical role in host defense against bacterial pathogens. Analysis of human TCGA database reveals many mutations of the Toll-Like Receptor 4 (TLR4) gene in human skin cancers. While it remains to be fully revealed what role PRRs play in response to increased environmental and commensal bacteria for carcinogenesis. Recently, we found a low number of spontaneous skin squamous cell carcinomas (SCCs) in 1-year-old Ikkaf/+K5Cre (IkkaKC/+) mice with specific Ikka reduction in keratinocytes. Interestingly, ablation of Tlr4 enhanced SCC numbers and sizes but reduced the latency of SCC development in IkkaKC/+;Tlr4-/- mice compared to IkkaKC/+ mice. Both spontaneous skin SCCs obtained from IkkaKC/+ and IkkaKC/+;Tlr4-/- mice showed loss of wild-type (WT) Ikka allele. IkkaKC/KC mice were previously known to develop spontaneous skin SCCs. Thus, we hypothesize that a skin condition with Ikka reduction in keratinocytes alters skin microbes and Tlr4 deletion further enhances this condition, resulting in loss of WT Ikka allele, which lead to increased spontaneous skin SCCs. Indeed, the bacterial numbers were increased in the skin of IkkaKC/+ mice compared to the skin of WT and Tlr4-/- mice and the bacterial numbers were further enhanced in the skin of IkkaKC/+;Tlr4-/- mice compared to IkkaKC/+ mice. These skin bacteria are Gram(+) firmicutes. Together, these results suggest that increased bacteria cause DNA damage-induced genomic instability, resulting loss of WT Ikka allele for spontaneous skin carcinogenesis. Currently, we are using organoid cultures to understand which pathways bacteria use impair the genome integrity in the skin with Ikka reduction or Ikka reduction/Tlr4 deletion as well as whether Tlr4 deletion impairs the activity of immune cells for fighting against bacterial pathogens. We are currently investigating their detailed mechanism.