Abstract
The dysregulation of caspase 4 (CASP4) expression is related to the occurrence, development, and outcome of many malignant tumors; however, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Herein, we investigated the expression of CASP4 in tumor tissues and its relationship with clinical prognosis, immune infiltration, and drug sensitivity status of ccRCC patients. Oncomine and The Cancer Genome Atlas (TCGA) databases were used to determine CASP4 mRNA expression in ccRCC patients. The correlation between CASP4 expression and disease prognosis was evaluated using Kaplan–Meier analysis. Related pathways were obtained from TCGA database via gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). Meanwhile, genes co-expressing with CASP4 in ccRCC were investigated. Finally, we analyzed the proportion of tumor-infiltrating immune cells (TICs) using the CIBERSORT computational method and assessed CASP4 methylation and its relationship with drug sensitivity. Immunohistochemical analysis of 30 paired ccRCC and adjacent normal tissues confirmed the in silico results. CASP4 mRNA expression in ccRCC was significantly higher than that in the normal tissues, positively correlated with clinicopathological features (clinical stage and pathological grade), and negatively correlated with patient overall survival (OS). GSEA and GSVA showed that the genes in the CASP4-high expression group were primarily enriched in immune-related activities. Moreover, CIBERSORT analysis of TIC proportions revealed that activated CD4 memory T cells were positively correlated with CASP4 expression. Notably, methylation analysis revealed that the abnormal upregulation of CASP4 might be caused by hypomethylation. Finally, we found that the abnormal expression of CASP4 may be related to tumor drug resistance. Overall, our study shows that CASP4 is overexpressed in ccRCC and is an important factor affecting disease prognosis. Hence, CASP4 may serve as a potential prognostic biomarker and therapeutic target in ccRCC.
Highlights
Kidney cancer is one of the most common malignancies of the urinary system, accounting for over 100,000 annual deaths worldwide, of which renal cell carcinoma (RCC) is responsible for more than 90% (Bray et al, 2018)
Considering the potential role of the association between the immune response and caspase 4 (CASP4) in Clear cell RCC (ccRCC) found in this study, as well as the reliable results obtained for immunotherapy in RCC, we further explored the infiltration of immune cells in ccRCC tumor tissues and the immune cells related to CASP4
Our study showed that CASP4 expression is upregulated in ccRCC patients and is significantly associated with a late clinical stage, a high pathological grade ccRCC, as well as a low survival rate
Summary
Kidney cancer is one of the most common malignancies of the urinary system, accounting for over 100,000 annual deaths worldwide, of which renal cell carcinoma (RCC) is responsible for more than 90% (Bray et al, 2018). Clear cell RCC (ccRCC) is the most common pathological form of RCC, accounting for 75–80% of cases, with a higher incidence in males than in females (Cohen and Mcgovern, 2005). Surgery is the first-line treatment for ccRCC in the early stage, with a 5-year survival rate after early surgery being approximately 70%. Approximately 30% of patients show relapse within five years after surgery (di Martino et al, 2018). The identification of novel molecular diagnostic markers can facilitate early diagnosis and expand our understanding of disease progression while providing potential targets for the treatment of ccRCC
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