Hennig Paulina, Turko Patrick, Di Filippo Michela, Levesque Mitchell P, Kündig Thomas, Beer Hans-Dietmar
Department of Dermatology, University Hospital Zurich, CH-8952, Schlieren, Switzerland.
Faculty of Medicine, University of Zurich, CH-8032, Zurich, Switzerland.
Cell Death Dis. 2025 Jul 1;16(1):465. doi: 10.1038/s41419-025-07785-9.
The inflammasome sensor NLRP1 is mainly expressed by epithelial cells including keratinocytes of human skin. Germline gain-of-function mutations in NLRP1 cause inflammatory skin syndromes and predispose patients to the development of cutaneous squamous cell carcinomas (cSCCs), a major type of skin cancer originating from keratinocytes. However, expression of NLRP1 is strongly reduced in cSCCs suggesting a complex role of the NLRP1 inflammasome in the development of this type of skin cancer. Suppression of NLRP1 expression in SCC cells is partially caused by an increase in p62 (SQSTM1), a cargo receptor for autophagy-dependent protein degradation. p62 is upregulated in numerous types of cancer and plays key roles in tumor development by activating different pathways. Here, we characterized the molecular mechanisms underlying suppression of NLRP1 expression by p62 in cSCCs. In SCC cells, NLRP1 activation is rescued by a knockdown or knockout of p62 mRNA and, consequently, protein expression, rather than by a knockout of p62 protein expression only. As these experiments suggest a regulation of NLRP1 by the p62 mRNA, we characterized p62 mRNA-regulated gene expression in SCC cells through RNA sequencing. In addition to mRNAs, we identified several differentially regulated microRNAs (miRs), including miR-34a-5p. These short non-coding RNAs regulate the stability or translation of mRNAs in a dynamic manner and a single miR can target multiple mRNAs. miR-34a-5p is an established tumor suppressor in different types of cancer and its expression is also downregulated in cSCCs. Although miR-34a-5p seems to bind neither p62 nor NLRP1 mRNA directly, it increases NLRP1 expression, most likely through an indirect and complex mechanism, which occurs at the RNA level. In summary, our findings revealed a novel pathway regulating suppression of the inflammasome sensor NLRP1 in SCC cells by p62, which occurs at the mRNA level and is mediated by miRs, including the tumor suppressive miR-34a-5p. Therefore, a pharmacological increase in miR-34a expression represents a treatment option for cSCC patients that allows not only to target know proteins regulated by miR-34a but also a reconstitution of NLRP1 expression.
炎性小体传感器NLRP1主要由包括人类皮肤角质形成细胞在内的上皮细胞表达。NLRP1的种系功能获得性突变会导致炎症性皮肤综合征，并使患者易患皮肤鳞状细胞癌（cSCC），这是一种起源于角质形成细胞的主要皮肤癌类型。然而，NLRP1在cSCC中的表达显著降低，这表明NLRP1炎性小体在这种皮肤癌的发生发展中具有复杂的作用。SCC细胞中NLRP1表达的抑制部分是由于自噬依赖性蛋白质降解的货物受体p62（SQSTM1）增加所致。p62在多种癌症类型中上调，并通过激活不同途径在肿瘤发展中起关键作用。在这里，我们阐述了cSCC中p62抑制NLRP1表达的分子机制。在SCC细胞中，通过敲低或敲除p62 mRNA，进而蛋白表达，而不仅仅是敲除p62蛋白表达，可挽救NLRP1的激活。由于这些实验表明p62 mRNA对NLRP1有调控作用，我们通过RNA测序对SCC细胞中p62 mRNA调控的基因表达进行了表征。除了mRNA，我们还鉴定了几种差异调控的微小RNA（miR），包括miR-34a-5p。这些短的非编码RNA以动态方式调节mRNA的稳定性或翻译，单个miR可以靶向多个mRNA。miR-34a-5p是不同类型癌症中公认的肿瘤抑制因子，其在cSCC中的表达也下调。尽管miR-34a-5p似乎既不直接结合p62也不结合NLRP1 mRNA，但它增加NLRP1表达，很可能是通过一种间接且复杂的机制，该机制发生在RNA水平。总之，我们的研究结果揭示了一种新的途径，即p62在mRNA水平通过包括肿瘤抑制性miR-34a-5p在内的miR介导，调控SCC细胞中炎性小体传感器NLRP1的抑制。因此，药理学上增加miR-34a的表达代表了一种针对cSCC患者的治疗选择，这不仅可以靶向由miR-34a调控的已知蛋白质，还可以恢复NLRP1的表达。
