Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Switzerland.
Institute for Molecular Health Sciences, Department of Biology, ETH Zürich, Zurich, Switzerland.
J Invest Dermatol. 2019 Aug;139(8):1788-1797.e6. doi: 10.1016/j.jid.2019.01.025. Epub 2019 Feb 7.
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-1β 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-1β and proIL-1α. Protein levels of NLRP1, ASC, caspase-1, and proIL-1β 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.
NLRP1 炎性小体蛋白是人类角质形成细胞中重要的先天免疫传感器，与 ASC 和半胱天冬酶-1 一起，介导促炎细胞因子 IL-1β 和 IL-18 的激活和分泌。这些细胞因子和炎性小体在小鼠肿瘤发生过程中可能具有部分相反的作用。相比之下，在人类的不同类型癌症中，ASC 的表达受损。在这项研究中，我们分析了炎性小体的激活和炎性小体蛋白的表达，包括它们的下游细胞因子，在鳞状细胞癌中，这是一种源自角质形成细胞的非黑色素瘤皮肤癌。我们评估了人原代角质形成细胞和皮肤癌衍生的 SCC 细胞系中的 mRNA 和蛋白质水平，并检测到 NLRP1 炎性小体成分的表达强烈下调，以及促炎细胞因子 proIL-1β 和 proIL-1α 的表达降低。与健康皮肤相比，来自患者的 SCC 活检样本中 NLRP1、ASC、半胱天冬酶-1 和 proIL-1β 的蛋白水平降低。此外，结果表明 PYCARD（ASC）、CASP1、IL1B 和 NLRP1 的表达在 SCC 细胞系中被甲基化沉默。总之，SCC 中炎性小体通路的下调可能有利于人类皮肤中晚期肿瘤的发展。
