Novel CARD11 mutations in human cutaneous squamous cell carcinoma lead to aberrant NF-κB regulation

Stephen A. Watt, Karin J. Purdie, Nicoline Y. den Breems, Michelle Dimon, Sarah T. Arron, Angela T. McHugh, Dylan J. Xue, Jasbani H. S. Dayal, Charlotte M. Proby, Catherine A. Harwood, Irene M. Leigh, Andrew P. South (Lead / Corresponding author)

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    Abstract

    NF-κB signaling plays a crucial role in regulating proliferation and differentiation in the epidermis. Alterations in the NF-κB pathway can lead to skin pathologies with a significant burden to human health such as psoriasis and cutaneous squamous cell carcinoma (cSCC). Caspase recruitment domain (CARD)-containing scaffold proteins are key regulators of NF-κB signaling by providing a link between membrane receptors and NF-κB transcriptional subunits. Mutations in the CARD family member, CARD14, have been identified in patients with the inflammatory skin diseases psoriasis and pityriasis rubra pilaris. Here, we describe that the gene coding for another CARD scaffold protein, CARD11, is mutated in more than 38% of 111 cSCCs, and show that novel variants outside of the coiled-coil domain lead to constitutively activated NF-κB signaling. CARD11 protein expression was detectable in normal skin and increased in all cSCCs tested. CARD11 mRNA levels were comparable with CARD14 in normal skin and CARD11 mRNA was increased in cSCC. In addition, we identified CARD11 mutations in peritumoral and sun-exposed skin, suggesting that CARD11-mediated alterations in NF-κB signaling may be an early event in the development of cSCC.

    Original languageEnglish
    Pages (from-to)2354-2363
    Number of pages10
    JournalAmerican Journal of Pathology
    Volume185
    Issue number9
    DOIs
    Publication statusPublished - Sep 2015

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    Watt, S. A., Purdie, K. J., den Breems, N. Y., Dimon, M., Arron, S. T., McHugh, A. T., Xue, D. J., Dayal, J. H. S., Proby, C. M., Harwood, C. A., Leigh, I. M., & South, A. P. (2015). Novel CARD11 mutations in human cutaneous squamous cell carcinoma lead to aberrant NF-κB regulation. American Journal of Pathology, 185(9), 2354-2363. https://doi.org/10.1016/j.ajpath.2015.05.018