Crosstalk of necroptosis and pyroptosis defines tumor microenvironment characterization and predicts prognosis in clear cell renal carcinoma

Abstract

Pyroptosis and necroptosis are two recently identified forms of immunogenic cell death in the tumor microenvironment (TME), indicating a crucial involvement in tumor metastasis. However, the characteristics of necroptosis and pyroptosis that define tumor microenvironment and prognosis in ccRCC patients remain unknown. We systematically investigated the transcriptional variation and expression patterns of Necroptosis and Pyroptosis related genes (NPRGs). After screening the necroptosis-pyroptosis clusters, the potential functional annotation for clusters was explored by GSVA enrichment analysis. The Necroptosis-Pyroptosis Genes (NPG) scores were used for the prognosis model construction and validation. Then, the correlations of NPG score with clinical features, cancer stem cell (CSC) index, tumor mutation burden (TMB), TME, and Immune Checkpoint Genes (ICGs) were also individually explored to evaluate the prognosis predictive values in ccRCC. Microarray screenings identified 27 upregulated and 1 downregulated NPRGs. Ten overall survival associated NPRGs were filtered to construct the NPG prognostic model indicating a better prognostic signature for ccRCC patients with lower NPG scores (P< 0.001), which was verified using the external cohort. Univariate and multivariate analyses along with Kaplan-Meier survival analysis demonstrated that NPG score prognostic model could be applied as an independent prognostic factor, and AUC values of nomogram from 1- to 5- year overall survival with good agreement in calibration plots suggested that the proposed prognostic signature possessed good predictive capabilities in ccRCC. A high-/sNPG score is proven to be connected with tumor growth and immune-related biological processes, according to enriched GO, KEGG, and GSEA analyses. Comparing patients with a high-NPG score to those with a low-NPG score revealed significant differences in clinical characteristics, growth and recurrence of malignancies (CSC index), TME cell infiltration, and immunotherapeutic response (P< 0.005), potentially making the NPG score multifunctional in the clinical therapeutic setting. Furthermore, AIM2, CASP4, GSDMB, NOD2, and RBCK1 were also found to be highly expressed in ccRCC cell lines and tumor tissues, and GASP4 and GSDMB promote ccRCC cells’ proliferation, migration, and invasion. This study firstly suggests that targeting the NPG score feature for TME characterization may lend novel insights into its clinical applications in the prognostic prediction of ccRCC.

Fatty acid metabolism-related lncRNAs are potential biomarkers for survival prediction in clear cell renal cell carcinoma

“…The research conducted by Dr Luo's team was the first to present extensive evidence of the substantial correlation between the prognosis prediction of ccRCC and the tumor environment, as characterized by necroptosis and pyroptosis. [49] The Necroptosis-Pyroptosis Genes (NPG) score has been found as a potential prognostic biomarker for ccRCC. The NPG score-based risk model accurately and consistently predicted the OS and tumor microenvironment of ccRCC.…”

Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma

“…Considering that a multitude of factors including age, ethnicity, and environmental factors influences patient survival, and the potential bias introduced by a survival analysis that solely addressed the correlation between DHODH expression and patient outcomes without accounting for multifactorial influences, additional studies are warranted. Moreover, by acknowledging the inherent limitations of relying solely on publicly available online databases for analysis and validation, further explorative, multicenter, prospective studies should be conducted 64 . In future studies, we aim to delve deeper into the specific mechanisms underlying the effect of DHODH on different stages of ccRCC development and validate its prognostic significance in patients with ccRCC through additional experimental designs and prospective studies.…”

CDKL3 shapes immunosuppressive tumor microenvironment and initiates autophagy in esophageal cancer

“…Our study found that patients with a high CrA risk score had higher infiltration levels of M2 macrophages based on the XCELL, CIBERSORT-ABS, and CIBERSORT algorithms. In another study, the Necroptosis-Pyroptosis Genes (NPG) scores established for prognostic prediction were found to be negatively correlated with infiltrating M2 Macrophage in patients with clear cell renal cell carcinoma (ccRCC) by the CIBERSOR algorithm ( 50 ). Moreover, this study showed that CDKL3 knockdown in KYSE150 cells could significantly inhibit autophagy induction in an autophagy-induced activated state.…”