Identification and validation of the pyroptosis-related genes signature based on immune microenvironment and molecular heterogeneity in prostate adenocarcinoma

Background: Pyroptosis may affect cancer progression by regulating the tumor microenvironment (TME) and biological function of cancer cells. The relationship between pyroptosis-related genes (PRGs) and prostate adenocarcinoma (PRAD) and its TME is unclear. Method: In our study, we carried out an overall bioinformatics analysis to build a prognostic PRGs model based on TME and molecular heterogeneity and external validation, then verified the relationship between PRGs and PRAD cells through cell experiments. The relationship between PRGs and tumor-immune cells, immune pathways, immune infiltration, cell-cell communication, genomic alteration tumor mutation burden, microsatellite-instability and drug sensitivity were analyzed. Results: A total of 36 PRGs were up- or down-regulated in PRAD. Functional enrichment analysis indicated that 33 PRGs were mostly involved in Salmonella infection, apoptosis and some signaling pathways (NOD-like receptor, C-type lectin receptor, AGE-RAGE, Cytosolic DNA-sensing, TNF and p53). We identified five prognostic genes (CHMP4C, PLGG1, TP53, GSDMB and PJVK) and constructed a PRGs model to predict progression free survival (PFS) in PRAD patients with high accuracy. And, it was verified with an external database. We found that there was a marked correlation between prognostic PRGs and immune cells, immune pathway, immune cell infiltration, tumor mutation burden and microsatellite instability. Finally, we increased the level of pyroptosis by LPS and established an RNA interference cell line. It was found that the protein expression of NT-GSDMD decreased. Meanwhile, knocking out the above genes affected their promotion of the proliferation of PRAD cells. The above experiments further showed that the five genes were indeed related to pyroptosis. Conclusion: We established PRGs signatures based on immune microenvironment and molecular heterogeneity through public data and verified them through external data and cell experiments. Our results might help to better understand the impact of proptosis on the progress of PRAD, and provided a new direction for the treatment of PRAD patients.