Role of Cytokines Released During Pyroptosis in Non-Small Cell Lung Cancer

Abstract

Purpose Pyroptosis is a recently discovered highly inflammatory form of programmed cell death, during which the N-terminus of the cleaved Gasdermin protein family forms pores in the cell membrane, leading to cell disintegration and the release of certain intracellular factors, including caspase3, gasdermin E (GSDME), and high mobility group proteins (HMGB1), which trigger a series of secondary inflammatory reactions. Specifically, caspase3 can lyse GSDME and induce pyrolysis, while HMGB1 is released passively after cell membrane destruction. In this study, the roles of these proteins in lung cancer tissues as well as their clinical significance were investigated. Patients and Methods The expression levels of GSDME, caspase3, and HMGB1 proteins in lung cancer and paracancerous tissues were determined via immunohistochemical staining, and their relationship with the clinical stage, pathological grade, and survival prognosis of the patients was analyzed. Further, CD8 + T cell accumulation in the above-mentioned tissues was also determined, and differences between them with respect to CD8 + T cell distribution were also investigated. Furthermore, the relationships between CD8 + T cell abundance and the expression levels of the above-mentioned proteins were determined via statistical analyses. Results Lung cancer and paracancerous tissues showed significantly different GSDME, caspase3, and HMGB1 protein expression levels. GSDME expression level and the presence or absence of lymph node invasion were identified as prognostic indicators of survival in patients with lung cancer. Surprisingly, however, HMGB1, which showed a certain level of correlation with the presence or absence of lymph node metastasis, could not be used as a prognostic indicator of survival. Conclusion GSDME may be an important prognostic indicator of survival in patients with lung cancer. However, the effects of HMGB1 expression level and CD8 + T cell abundance on the prognosis of patients with lung cancer still need further investigation.

The multifaceted roles of GSDME-mediated pyroptosis in cancer: therapeutic strategies and persisting obstacles

“…Lung cancer is the most ubiquitous and lethal malignancy worldwide [ 103 ]. Recent mechanistic work revealed that GSDME knockdown can trigger the transition from apoptosis-to-pyroptosis in lung cancer lines, confirming the hypothesis that GSDME expression determines the type of cell death in caspase-3-activated tumor cells [ 104 ]. In A549 cells, dasatinib can trigger pyroptosis and elevate GSDME levels in A549 cells without the involvement of p53 [ 105 ].…”

A novel association of pyroptosis-related gene signature with the prognosis of hepatocellular carcinoma

“…(B) Immunohistochemistry of the CHMP4A, HMGB1 and PLK1 was determined in HCC tissues and normal tissues from the HPA database. (41). In breast cancer, HMGB1 translocation was demonstrated to be associated with pyroptosis (42).…”

“…Moreover, HMGB1 functioned as the executor of pyroptotic cell death to participate in the regulation of tumor immune microenvironment via the inhibition of mutant BRAF and MEK ( 40 ). High expression of HMGB1 was found in lung cancer tissues, and its release upon pyroptotic cell destruction could be used as a prognostic marker of survival ( 41 ). In breast cancer, HMGB1 translocation was demonstrated to be associated with pyroptosis ( 42 ).…”

Pyroptosis: A new insight of non-small-cell lung cancer treatment

“…The above results indicated that GSDMD can be regard as an independent prognostic biomarker in LUAD patients. Meanwhile, the expression level of GSDME in lung cancer tissue is significantly higher than that in adjacent tissue, patients with lung cancer having a high GSDME expression have less lymph node metastasis and longer postoperative survival, although the decrease in GSDME level was not significantly correlated with tumor size, clinical stage, age, or tumor recurrence rate (55,110). In addition, the expression level of GSDME was positively correlated with that of caspase-3, and hence caspase-3 is also an important prognostic biomarker in lung cancer patients (55).…”