Comprehensive Analysis of the Immune Infiltrates of Pyroptosis in Kidney Renal Clear Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Sun Z
PROVIDER: S-EPMC8459616 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Increasing evidence has indicated that pyroptosis could regulate the tumor immune microenvironment (TIME) to affect the tumor development. As a highly immunogenic tumor, clear cell renal cell carcinoma (ccRCC) can benefit from immunotherapy, but related research on pyroptosis in the TIME of ccRCC is still deficient. METHODS:Available data derived from TCGA and GEO databases were analyzed to identify the different expression profiles of pyroptosis in ccRCC and normal tissues, and the correlation of pyroptosis regulators with TIME was evaluated in ccRCC. RESULTS:According to consensus clustering analysis, two differential expression levels of subtypes were identified to affect patient prognosis, and were related to histological tumor stage and grade. Immune cells were calculated by the CIBERSORT algorithm. Higher infiltrated levels of B cells naive, T cells CD4 memory resting, NK cells resting, monocytes, macrophages were observed in Cluster 1, while higher infiltrated levels of CD8+ T cells, T follicular helper cells, and Tregs were observed in Cluster 2. Gene set enrichment analysis indicated that Cluster 2 was enriched in multiple immune-related pathways, including the JAK-STAT signaling pathway. Moreover, overexpression of eight immune checkpoints was related to ccRCC development, especially in Cluster 2. As four potentially key pyroptosis regulators, AIM2, CASP5, NOD2, and GZMB were confirmed to be upregulated in ccRCC by RT-qPCR analysis and further verified by the HPA database. Further pan-cancer analysis suggested that these four pyroptosis regulators were differentially expressed and related to the TIME in multiple cancers. CONCLUSION:The present study provided a comprehensive view of pyroptosis regulators in the TIME of ccRCC, which may provide potential value for immunotherapy.
| S-EPMC8670029 | biostudies-literature
Project description:Kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) are the most common RCC types. RCC has high immune infiltration levels, and immunotherapy is currently one of the most promising treatments for RCC. Collagen triple helix repeat containing 1 (CTHRC1) is an extracellular matrix protein that regulates tumor invasion and modulates the tumor microenvironment. However, the association of CTHRC1 with the prognosis and tumor-infiltrating lymphocytes of KIRP and KIRC has not been reported. We examined the CTHRC1 expression differences in multiple tumor tissues and normal tissues via exploring TIMER, Oncomine, and UALCAN databases. Then, we searched the Kaplan-Meier plotter database to evaluate the correlation of CTHRC1 mRNA level with clinical outcomes. Subsequently, the TIMER platform and TISIDB website were chosen to assess the correlation of CTHRC1 with tumor immune cell infiltration level. We further explored the causes of aberrant CTHRC1 expression in tumorigenesis. We found that CTHRC1 level was significantly elevated in KIRP and KIRC tissues relative to normal tissues. CTHRC1 expression associates with tumor stage, histology, lymph node metastasis, and poor clinical prognosis in KIRP. The CTHRC1 level correlates to tumor grade, stage, nodal metastasis, and worse survival prognosis. Additionally, CTHRC1 is positively related to different tumor-infiltrating immune cells in KIRP and KIRC. Moreover, CTHRC1 was closely correlated with the gene markers of diverse immune cells. Also, high CTHRC1 expression predicted a worse prognosis in KIRP and KIRC based on immune cells. Copy number variations (CNV) and DNA methylation might contribute to the abnormal upregulation of CTHRC1 in KIRP and KIRC. In conclusion, CTHRC1 can serve as a biomarker to predict the prognosis and immune infiltration in KIRP and KIRC.
| S-EPMC7898899 | biostudies-literature
Project description:There has been an increase in the mortality rate and morbidity of kidney cancer (KC) with kidney renal clear cell carcinoma (KIRC) being the most common subtype of KC. GRAMD1C (GRAM Domain Containing 1C) has not been reported to relate to prognosis and immunotherapy in any cancers. Using bioinformatics methods, we judged the prognostic value of GRAMD1C expression in KIRC and investigated the underlying mechanisms of GRAMD1C affecting the overall survival of KIRC based on data downloaded from The Cancer Genome Atlas (TCGA). The outcome revealed that reduced GRAMD1C expression could be a promising predicting factor of poor prognosis in kidney renal clear cell carcinoma. Meanwhile, GRAMDIC expression was significantly correlated to several tumor-infiltrating immune cells (TIICs), particularly the regulatory T cells (Tregs). Furthermore, GRAMD1C was most significantly associated with the mTOR signaling pathway, RNA degradation, WNT signaling pathway, toll pathway and AKT pathway in KIRC. Thus, GRAMD1C has the potential to become a novel predictor to evaluate prognosis and immune infiltration for KIRC patients.
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Project description:BackgroundPhosphoinositide 3-kinases (PI3Ks) are lipid enzymes that regulate a wide range of intracellular functions. In contrast to Class I and Class III PI3K, which have more detailed descriptions, Class II PI3K has only recently become the focus of functional research. PIK3C2A is a classical member of the PI3Ks class II. However, the role of PIK3C2A in cancer prognosis and progression remains unknown.MethodsThe expression pattern and prognostic significance of PIK3C2A in human malignancies were investigated using multiple datasets and scRNA-seq data. The PIK3C2A expression in renal clear cell carcinoma (KIRC) was then validated utilizing Western blot. The functional role of PIK3C2A in KIRC was assessed using combined function loss experiments with in vitro experiments. Furthermore, the correlation of PIK3C2A expression with tumor immunity was investigated in KIRC. The TCGA database was employed to investigate PIK3C2A functional networks.ResultsSignificant decrease in PIK3C2A expression in KIRC, demonstrated that it potentially influences the prognosis of diverse tumors, particularly KIRC. In addition, PIK3C2A was significantly correlated with the T stage, M stage, pathologic stage, and histologic grade of KIRC. Nomogram models were constructed and used to predict patient survival based on the results of multivariate Cox regression analysis. PIK3C2A knockdown resulted in significantly increased KIRC cell proliferation. Of note, PIK3C2A expression demonstrated a significant correlation with the infiltrating levels of primary immune cells in KIRC.ConclusionThese findings support the hypothesis that PIK3C2A is a novel biomarker for tumor progression and indicates dynamic shifts in immune infiltration in KIRC. Furthermore, aberrant PIK3C2A expression can influence the biological activity of cancer cells.
| S-EPMC10098324 | biostudies-literature
Project description: Not available
| S-EPMC10691167 | biostudies-literature
Project description:BackgroundPseudogenes played important roles in tumorigenesis, while there are nearly no reports about the expression and roles of HSPA7 in the cancer.MethodsFirstly, we used Logistic regression, the KS test, the GEPIA database, UALCAN database and qRT-PCR to analyze the expression level of HSPA7 in KIRC, then we used the Cox regression and the Kaplan-Meier curve to analyze the overall survival (OS) of KIRC patients with different Clinico-pathological parameters. Thirdly, we used the multivariate Cox analysis of influencing factors to compare the correlation between the HSPA7 expression level and the clinical parameters. Finally, we used multi-GSEA analysis and the Tumor Immunoassay Resource (TIMER) database to explore the functional role of HSPA7 in KIRC RESULTS: The HSPA7 is highly expressed in KIRC tumor tissues, and its expression is related to clinico-pathological features and survival in KIRC patients. GSEA analysis displayed the high expression of HSPA7 in KIRC were related to several tumor-related and immune-related pathways. With the TIMER database analysis we showed that HSPA7 levels were correlated with the CD4+ T cells, neutrophils and Dendritic Cell.ConclusionsOur study showed that HSPA7 is very important in the tumor progression and may act as a poor prognostic biomarker for KIRC tumor by modulating immune infiltrating cells.
| S-EPMC8375184 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is a common urinary system malignant tumor with a high incidence and recurrence rate. Pyroptosis is a kind of programmed cell death caused by inflammasomes. More and more evidence had confirmed that pyroptosis plays a very significant part in cancer, and it is controversial whether pyroptosis promotes or inhibits tumors. Consistently, its potential role in ccRCC treatment efficacy and prognosis remains unclear. In this study, we systematically investigated the role of pyroptosis in the ccRCC samples from The Cancer Genome Atlas (TCGA) database. Based on the differentially expressed pyroptosis-related genes (DEPRGs), we identified three pyroptosis subtypes with different clinical outcomes, immune signatures, and responses to immunotherapy. Gene set variation analysis (GSVA), Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that pyroptosis activation meant infiltration of more immune cells that is conducive to tumor progression. To further investigate the immunomodulatory effect of pyroptosis in ccRCC, we constructed a pyroptosis-score based on the common differential prognostic genes of the three pyroptosis subtypes. It was found that patients with high pyroptosis-score were in an unfavorable immune environment and the prognosis was worse. Gene set enrichment analysis suggested that immune-related biological processes were activated in the high pyroptosis-score group. Then, the least absolute shrinkage and selection operator (LASSO) Cox regression was implemented for constructing a prognostic model of eight pyroptosis-related long noncoding RNAs (PRlncRNAs) in the TCGA dataset, and the outcomes revealed that, compared with the low-risk group, the model-based high-risk group was intently associated with poor overall survival (OS). We further explored the relationship between high- and low-risk groups with tumor microenvironment (TME), immune infiltration, and drug therapy. Finally, we constructed and confirmed a robust and reliable PRlncRNA pairs prediction model of ccRCC, identified PRlncRNA, and verified it by experiments. Our findings suggested the potential role of pyroptosis in ccRCC, offering new insights into the prognosis of ccRCC and guiding effectual targeted therapy and immunotherapy.
| S-EPMC9277062 | biostudies-literature
Project description:BackgroundMammalian STE20-like kinase 1 (MST1/STK4/KRS2) is a highly conserved serine/threonine kinase and a central member of the Hippo signaling pathway. STK4 has been reported to play important roles in various tumors, but a systematic and comprehensive study of its function in clear cell renal cell carcinoma (ccRCC) has not been conducted.MethodsIn this study, we used immunohistochemistry (IHC), western blot (WB), quantitative real-time PCR (qPCR) experiments, and bioinformatics analysis to comprehensively analyze the expression, prognostic value, and immune infiltration of STK4 in ccRCC.ResultsAnalysis of the TCGA database showed that the expression level of the STK4 gene in ccRCC patients depended on tumor stage, grade, and distant lymphatic metastasis. This was further confirmed by the results of IHC, WB, and qPCR. In addition, we used the receiver operating characteristic curve (ROC curve) to elucidate the diagnostic value of STK4 in ccRCC patients. According to the findings of the TIMER database, the high expression of STK4 is significantly associated with the survival of kidney cancer (including ccRCC) patients (p < 0.001), suggesting that STK4 is a reliable prognostic predictor. We then used gene set enrichment analysis (GSEA) to explore the mechanisms behind STK4 function in ccRCC. We found that STK4 may play a role in immune regulation interactions. Subsequently, we performed immune infiltration analysis of STK4. The results showed that STK4 may regulate the development of ccRCC by affecting the immune infiltration of NK and pDC cells.ConclusionsSTK4 may be a prognostic marker for ccRCC and may help identify new strategies for treating ccRCC patients.
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Project description:Background The tumor-suppressive role of protein tyrosine phosphatase receptor type O (PTPRO) has been described in a variety of human cancers; however, the clinical significance of PTPRO in human clear cell renal cell carcinoma (ccRCC) remains unclear. Methods PTPRO expression in renal cell carcinoma (RCC) was analyzed via the Oncomine database, Gene Expression Omnibus (GEO) datasets, and The Cancer Genome Atlas (TCGA) datasets. The Kaplan-Meier curves and Cox proportional hazards model were used to evaluate the relationship of PTPRO with overall survival in ccRCC. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) were performed to explore the signaling pathways in which PTPRO may be involved. The correlation between PTPRO and immune infiltrates in ccRCC was investigated via Tumor Immune Estimation Resource (TIMER) database. The association between PTPRO mRNA expression and its methylation in RCC was analyzed using the Cancer Cell Line Encyclopedia (CCLE) dataset, GEO dataset, and cBioPortal database. The impact of PTPRO methylation on overall survival was estimated by the MethSurv database. Results We showed that the expression of PTPRO was significantly lower in human RCC. Moreover, the lower expression of PTPRO was associated with worse overall survival in ccRCC, particularly in the advanced stage patients. Multivariate Cox regression analysis revealed the expression of PTPRO as an independent prognostic predictor for overall survival of ccRCC. Of note, PTPRO was found to be associated with the activation of immune signaling and immune cell infiltration. Furthermore, methylation of PTPRO was prevalently observed in ccRCC, and methylation of PTPRO predicted the poor outcome of ccRCC. Conclusions Our findings suggested that PTPRO at both RNA and DNA methylation levels had the potential as a prognostic biomarker for predicting prognosis, and PTPRO expression was closely associated with immune infiltration in ccRCC patients.
| S-EPMC8798001 | biostudies-literature
Project description:Gasdermin B (GSDMB) is part of the gasdermin (GSDM) family, and they use varying means of domain interactions in molecules to adjust their pore-forming and lipid-binding actions. The GSDM family has roles in the regulation of cell differentiation and proliferation, particularly in the process of pyroptosis. Nonetheless, the correlation of GSDMB with immune infiltrates and its prognostic values in clear cell renal cell carcinoma (ccRCC) are still undefined. Therefore, we assessed the correlation of GSDMB with immune infiltrates and its prognostic role in ccRCC. The transcriptional expression profiles of GSDMB in ccRCC tissues in addition to normal tissues were retrieved from The Cancer Genome Atlas (TCGA) and additionally verified in a different independent cohort, which was obtained from the Gene Expression Omnibus (GEO) database. The Human Protein Atlas and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) were used to assess the protein expression of GSDMB. To assess the effectiveness of GSDMB in distinguishing ccRCC from normal samples, the receiver operating characteristic (ROC) curve analysis was performed. Relationships between GSDMB expression, clinicopathological variables, and overall survival (OS) were evaluated with multivariate methods as well as Kaplan-Meier survival curves. Protein-protein interaction (PPI) networks were created with STRING. Functional enrichment analyses were conducted by utilizing the "ClusterProfiler" package. The Tumor Immune Estimation Resource (TIMER) and tumor-immune system interaction database (TISIDB) were utilized to determine the association between the mRNA expression of GSDMB and immune infiltrates. GSDMB expression was significantly more upregulated in ccRCC tissues compared to surrounding normal tissues. An increase in the mRNA expression of GSDMB was related to the high pathologic stage and advanced TNM stage. The analysis of the ROC curve indicated that GSDMB had an AUC value of 0.820 to distinguish between ccRCC tissues and adjacent normal controls. Kaplan-Meier survival analysis indicated that ccRCC patients with high GSDMB had a poorer prognosis compared to those with low GSDMB (P < 0.001). Correlation analysis showed that the mRNA expression of GSDMB was associated with immune infiltrates and the purity of the tumor. Upregulation of GSDMB is significantly related to immune infiltrates and poor survival in ccRCC. The results of this study indicate that GSDMB could be regarded as a biomarker for the detection of poor prognosis and potential target of immune treatment in ccRCC.
| S-EPMC8702340 | biostudies-literature