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Sand, Jennifer, Fenini, Gabriele, Grossi, Serena, Hennig, Paulina, Di Filippo, Michela, Levesque, Mitchell, Werner, Sabine, French, Lars E. and Beet, Hans-Dietmar (2019): The NLRP1 Inflammasome Pathway Is Silenced in Cutaneous Squamous Cell Carcinoma. In: Journal of Investigative Dermatology, Vol. 139, No. 8

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The inflammasome protein NLRP1 is an important innate immune sensor in human keratinocytes, and, together with ASC and caspase-1, it mediates the activation and secretion of the proinflammatory cytokines IL-1 beta and IL-18. These cytokines and inflammasomes can have partly opposing roles during tumorigenesis in mice. In contrast, ASC expression is impaired in different types of cancer in humans. In this study, we analyzed inflammasome activation and expression of inflammasome proteins, including their downstream cytokines, in squamous cell carcinomas, a type of nonmelanoma skin cancer derived from keratinocytes. We assessed mRNA and protein levels in human primary keratinocytes and skin carcinoma-derived SCC cell lines and detected a strong down-regulation of expression of NLRP1 inflammasome components, as well as reduced expression of the proinflammatory cytokines proIL-1 beta and proIL-1 alpha. Protein levels of NLRP1, ASC, caspase1, and proIL-1 beta were reduced in patient-derived SCC biopsy samples compared with healthy skin. Furthermore, the results suggest that expression of PYCARD (ASC), CASP1, IL1B, and NLRP1 is silenced by methylation in SCC cell lines. In conclusion, the down-regulation of the inflammasome pathway in SCCs might favor late tumor development in human skin.

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