Novel model of pyroptosis-related molecular signatures for prognosis prediction of clear cell renal cell carcinoma patients

Background: Pyroptosis is a programmed death mode of inflammatory cells, which is closely related to tumor progression and tumor immunity.Clear cell renal cell carcinoma (ccRCC) is the major pathological type of renal cell carcinoma (RCC) with poor prognosis.Many theories have tried to clarify the mechanism in the development of ccRCC, but the role of pyroptosis in ccRCC has not been well described.The main purpose of this study is to explore the role of pyroptosis in ccRCC and establish a novel prognosis prediction model of pyroptosis-related molecular signatures for ccRCC.Methods: In the present study, we made a systematical analysis of the association between ccRCC RNA transcriptome sequencing data from The Cancer Genome Atlas (TCGA) database [which included 529 ccRCC patients who were randomized in a training cohort (n=265) and an internal validation cohort (n=264)] and 40 pyroptosis-related genes (PRGs), from which four genes (CASP9, GSDME, IL1B and TIRAP) were selected to construct a molecular prediction model of PRGs for ccRCC.In addition, a cohort of 114 ccRCC patients from Shanghai Eastern Hepatobiliary Surgery Hospital (EHSH) was used as external data to verify the effectiveness of the model by immunohistochemistry.Moreover, the biological functions of the four PRGs were also verified in ccRCC 786-O and 769-P cells by Western blot (WB), CCK-8 cell proliferation, and Transwell invasion assays.Results: The model was able to differentiate high-risk patients from low-risk patients, and this differentiation was consistent with their clinical survival outcomes.In addition, the four PRGs also affected the ability of cell proliferation and invasion in ccRCC.Conclusion: The prediction model of pyroptosis-related molecular markers developed in this study may prove to be a novel understanding for ccRCC.