AUTHOR=Meng Lingfeng , Tian Zijian , Long Xingbo , Diao Tongxiang , Hu Maolin , Wang Miao , Zhang Wei , Zhang Yaoguang , Wang Jianye , He Yuhui 

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

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.600248

DOI=10.3389/fgene.2020.600248

ISSN=1664-8021

ABSTRACT=<p>The dysregulation of caspase 4 (<italic>CASP4</italic>) 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 <italic>CASP4</italic> 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 <italic>CASP4</italic> mRNA expression in ccRCC patients. The correlation between <italic>CASP4</italic> 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 <italic>CASP4</italic> in ccRCC were investigated. Finally, we analyzed the proportion of tumor-infiltrating immune cells (TICs) using the CIBERSORT computational method and assessed <italic>CASP4</italic> methylation and its relationship with drug sensitivity. Immunohistochemical analysis of 30 paired ccRCC and adjacent normal tissues confirmed the <italic>in silico</italic> results. <italic>CASP4</italic> 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 <italic>CASP4</italic>-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 <italic>CASP4</italic> expression. Notably, methylation analysis revealed that the abnormal upregulation of <italic>CASP4</italic> might be caused by hypomethylation. Finally, we found that the abnormal expression of <italic>CASP4</italic> may be related to tumor drug resistance. Overall, our study shows that <italic>CASP4</italic> is overexpressed in ccRCC and is an important factor affecting disease prognosis. Hence, <italic>CASP4</italic> may serve as a potential prognostic biomarker and therapeutic target in ccRCC.</p>