Pyroptosis is a type of programmed lytic cell death mechanism associated with the activation of inflammasomes and inflammatory 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 non-malignant 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 in UCEC patients among the members of the protein family was observed for GSDME which also showed the most significant 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 histotype-dependent expression of the most of gasdermin family of 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.
Gastric tumors are the third leading cause of cancer-related mortality worldwide. This study investigates the effects of Notch signaling pathway dysregulations during gastric carcinogenesis. Hence, the signatures relevant to Notch signaling pathways were collected from the molecular signatures database, and their expression patterns in available mRNA expression profiles of gastric cancer cohorts were explored using a Z score-based pathway activation scoring method. The results of this study uncover that the Notch signaling pathway signatures are dysregulated highly in diffuse subtype-specific gastric cancer rather than intestinal subtype tumors. In addition, ontological functional analysis reveals that Notch signaling involves extracellular matrix structure and complex organization, collagen structure and trimer biosynthesis during their proliferation, survival, and metastasis. The identified pathway dysregulation is further reconfirmed by examining ROC curves of Notch receptor isoform genes such as NOTCH1, NOTCH2, NOTCH3, and NOTCH4, which could prognostic the diffuse subtype-specific gastric tumors with better specificity and sensitivity with greater areas under the curve (AUC) values. Additionally, overall survival (OS) studies also reassured that these gene expressions reveal poor survival patterns associated with highly expressed conditions in diffuse subtypes of gastric cancer patients with significant p-values (p < 0.05). The results of the genomics drug sensitivity in cancer (GDSC) profile show that ERK and MAPK inhibitors are prominent drug targets for this signaling pathway dysregulations in the corresponding subtype of gastric tumors. Thus, the current findings would benefit the development of drug treatments in diffuse subtype-specific gastric carcinogenesis.
The mechanism governing the stabilization of the replication fork under replication stress is pivotal for maintaining genomic integrity and cellular viability. In this context, the safeguard factors BRCA1/2 and nucleases engage in a regulatory equilibrium, modulating the extent of nascent strand end resection—a process vital for replication fork stabilization under stress and for fork restart upon stress released. The recruitment dynamics of these nucleases, however, remain to be elucidated. Recent two independent studies by