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. 2021 Jan 14:11:600248.
doi: 10.3389/fgene.2020.600248. eCollection 2020.

Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining

Lingfeng Meng  1   2 , Zijian Tian  1   2 , Xingbo Long  1 , Tongxiang Diao  1 , Maolin Hu  1 , Miao Wang  1 , Wei Zhang  1 , Yaoguang Zhang  1 , Jianye Wang  1   2 , Yuhui He  3
Affiliations

Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining

Lingfeng Meng et al. Front Genet. .

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.

Keywords: CD4 memory T cells; caspase 4; clear cell renal cell carcinoma; overexpression; prognosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
CASP4 expression in clear cell renal cell carcinoma (ccRCC) patients and its relationship with prognosis: Data retrieved from The Cancer Genome Atlas database. (A) Difference in the expression of CASP4 between ccRCC and normal tissues. (B) The overall survival (OS) of patients with high CASP4 expression was significantly lower than that of patients with low CASP4 expression. The shaded area represents the 95% confidence interval.
FIGURE 2
FIGURE 2
Immunohistochemistry staining of caspase 4 (CASP4) in clear cell renal cell carcinoma (ccRCC) and adjacent normal tissues. (A) High CASP4 expression in ccRCC tissues; (B) low CASP4 expression in ccRCC tissues; and (C) low CASP4 expression in adjacent normal tissues.
FIGURE 3
FIGURE 3
Survival of patients with different caspase 4 (CASP4) expression levels based on an external dataset. (A) Based on the H-Scores for CASP4, the overall survival of high-risk patients was significantly lower than that of low-risk patients. The shaded area represents the 95% confidence interval. (B) Kaplan–Meier analysis of patients with high and low expression of CASP4 in the OSkirc.
FIGURE 4
FIGURE 4
Clinicopathological significance of caspase 4 (CASP4) expression. Expression of CASP4 as a function of (A) pathological grade, (B) clinical stage, (C) T stage, (D) N stage, (E) M stage, (F) age, and (G) sex.
FIGURE 5
FIGURE 5
Gene set enrichment analysis and gene set variation analysis of CASP4 expression in data retrieved from The Cancer Genome Atlas dataset. (A) Gene set enrichment analysis and (B) gene set variation analysis. Only signaling pathways with a log2 (fold-change) > 0.2 are shown.
FIGURE 6
FIGURE 6
Relationships between CASP4 expression and that of multiple genes. (A) CASP1; (B) GMIP; (C) APOBEC3G; (D) MILR1; (E) LPXN; (F) DYNLL2; (G) CTDSPL; (H) NDRG2; (I) HYAL1; (J) WLS; and (K) Circle diagram of the expression relationship between genes.
FIGURE 7
FIGURE 7
Distribution of tumor-infiltrating immune cells (TICs) in tumor samples and their correlation with CASP4 expression. (A) Proportion of 22 types of TICs in ccRCC tumor samples. (B) Ratio differentiation of the 22 types of immune cells in patients with high and low expression of CASP4. (C) The median value of the fraction of CD8 T cells showed no significant difference in the survival curves of the high and low fraction groups. The shaded area represents the 95% confidence interval. (D) Correlation of the proportion of five types of TICs and the expression of CASP4; (E) Venn plot is shown.
FIGURE 8
FIGURE 8
Methylation analysis of the CASP4 gene and its relationship with drug sensitivity. Detection of methylation levels in clear cell renal cell carcinoma and para-cancerous normal tissues based on DiseaseMeth 2.0 (A). Using NCI-60 cell line-derived data, Pearson correlation tests were performed to analyze the relationship between the expression of CASP4 and drug sensitivity (B).
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