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BackgroundEmerging evidence suggests an important role for pyroptosis in tumorigenesis and recurrence, but it remains to be elucidated in prostate cancer (PCa). Considering the low accuracy of common clinical predictors of PCa recurrence, we aimed to develop a novel pyroptosis-related signature to predict the prognosis of PCa patients based on integrative analyses of bulk and single-cell RNA sequencing (RNA-seq) profiling.MethodsThe RNA-seq data of PCa patients was downloaded from several online databases. PCa patients were stratified into two Classes by unsupervised clustering. A novel signature was constructed by Cox and the Least Absolute Shrinkage and Selection Operator (LASSO) regression. The Kaplan-Meier curve was employed to evaluate the prognostic value of this signature and the single sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to analysis tumor-infiltrating immune cells. At single-cell level, we also classified the malignant cells into two Classes and constructed cell developmental trajectories and cell-cell interaction networks. Furthermore, RT-qPCR and immunofluorescence were used to validate the expression of core pyroptosis-related genes.ResultsTwelve prognostic pyroptosis-related genes were identified and used to classify PCa patients into two prognostic Classes. We constructed a signature that identified PCa patients with different risks of recurrence and the risk score was proven to be an independent predictor of the recurrence free survival (RFS). Patients in the high-risk group had a significantly lower RFS (P<0.001). The expression of various immune cells differed between the two Classes. At the single-cell level, we classified the malignant cells into two Classes and described the heterogeneity. In addition, we observed that malignant cells may shift from Class1 to Class2 and thus have a worse prognosis.ConclusionWe have constructed a robust pyroptosis-related signature to predict the RFS of PCa patients and described the heterogeneity of prostate cancer cells in terms of pyroptosis.

ObjectiveProstate cancer (PCa) severely affects men's health worldwide. The mechanism of methyltransferase‐like 3 (METTL3) in affecting PCa development by regulating miR‐148a‐3p expression via N6‐methyladenosine (m6A) modification was investigated.MethodsMETTL3, miR‐148a‐3p, and thioredoxin interacting protein (TXNIP) levels were determined using RT‐qPCR and Western blotting. The m6A modification level of miR‐148a‐3p was observed by Me‐RIP assay. Bioinformatics website predicted miR‐148a‐3p and TXNIP levels in PCa and their correlation, and the binding site between them was verified by dual‐luciferase assay. The proliferation, migration, invasion, and apoptosis of PCa cells were examined by CCK‐8 assay, Transwell assay, and flow cytometry. A transplanted tumor model was established in nude mice to observe the tumor growth ability, followed by determination of TXNIP levels in tumor tissues by immunohistochemistry.ResultsMETTL3 interference restrained the proliferation, migration, and invasion and promoted apoptosis of PCa cells. METTL3 up‐regulated miR‐148a‐3p by promoting the m6A modification of pri‐miR‐148a‐3p in PCa cells. miR‐148a‐3p overexpression nullified the inhibitory actions of silencing METTL3 on PCa cell growth. miR‐148a‐3p facilitated PCa cell growth by silencing TXNIP. METTL3 interference inhibited tumor growth by down‐regulating miR‐148a‐3p and up‐regulating TXNIP.ConclusionMETTL3 promoted miR‐148a‐3p by mediating the m6A modification of pri‐miR‐148a‐3p, thereby targeting TXNIP, interfering with METTL3 to inhibit the proliferation, migration and invasion of PCa cells, promote apoptosis, and inhibit tumor growth in nude mice.