Pyroptosis is a type of programmed lytic cell death mechanism associated with the activation of in ammasomes and in ammatory caspases, proteolytic cleavage of gasdermin proteins (GSDMA-E and PJVK), resulting in the formation of pores in cellular membranes such as plasma membrane and mitochondrial membranes. Here, I show that GSDMC expression was increased, GSDME (DFNA5) and PJVK (DFNB59) expression were decreased in uterine corpus endometrial carcinoma (UCEC) cells compared to normal endometrial cells. Total percentage of patients affected by mutations in gasdermin family of genes was the highest in UCEC compared to other cancer types. The highest mutation percentage among the members of the protein family was observed for GSDME which also showed the most signi cant difference in the mRNA expression among other family members between tumor and normal samples, possibly pointing to its relatively higher importance in the pathogenesis of UCEC.Gasdermin family of genes (except GSDMA) had higher transcript levels in serous endometrial adenocarcinoma than in endometrioid endometrial adenocarcinoma, demonstrating the histotypedependent expression of the most of gasdermin genes in UCEC. Transcript levels of certain gasdermin family members also differed based on residual tumor status and histologic tumor grade; however, the expression of any gasdermin genes did not change depending on menopause status. This study suggests that a better mechanistic understanding of pyroptotic cell death in uterine corpus endometrial carcinoma might help identify novel therapeutic targets for the management of this gynecological malignancy.
Signi cance StatementUterine corpus endometrial carcinoma (UCEC) is the second most common gynecological malignancy.Pyroptosis is a highly immunogenic cell death mechanism with the potential to activate anti-tumor immunity, and it is mediated by pore-forming gasdermin proteins. In this study, I showed that the expression of certain members of the gasdermin family changes in UCEC, and that the percentage of patients affected by mutations in gasdermin family of genes is the highest in UCEC compared to other cancer types, showing the relatively higher importance of pyroptotic cell death in UCEC. Besides, I found that most gasdermin genes show histotype-dependent expression, with potential implications in prognosis. Collectively, this study suggests that pyroptosis needs to be better understood in the context of UCEC.
