Comprehensive Investigation of Genes Associated with Cell Cycle Pathways for Prognosis and Immunotherapy in Bladder Urothelial Carcinoma.

Abstract

Bladder urothelial carcinoma (BLCA) is estimated to cause approximately 150,000 deaths per year worldwide. The prognosis of BLCA remains dismal, so early detection can have a significant impact on clinical outcomes. Numerous studies have shown that genes can alter the progression of tumors by regulating cell cycle, thus achieving targeted therapy. A comprehensive comparison analysis of expression profiles in BLCA datasets downloaded from Gene Expression Omnibus (GEO) was conducted to identify common differentially expressed genes (DEGs) using R packages. Gene Set Enrichment Analysis (GSEA) of identified DEGs was performed, and a protein-protein interaction (PPI) network was mapped using Cytoscape software. The expression of hub genes was validated in GEPIA2, cBioPortal, and ONCOMINE databases. The potential roles of the cell cycle genes (CCGs) in immunity were also explored. A total of 70 DEGs from GSE13507, GSE37815, and GSE52519 were identified commonly, including 23 up-regulated and 47 down-regulated genes. GSEA and PPI analysis revealed genes in the cell cycle pathway significantly enriched in tumor tissues, and the expression of 12 CCGs was up-regulated. Furthermore, significant differences of the CCGs expression were found in different immune subtypes of BLCA. The expression of CCGs was closely related to CD4+ T cell, memory B cell, eosinophil, monocyte, T helper cell, and many marker genes of immunomodulators. Abundance of tumor-infiltrating lymphocytes were associated with patients' overall survival with BLCA. Increased CCG expression was correlated with better prognosis in BLCA patients, together with higher immune infiltration levels in CD4 T activated memory cell, and CD8 T central cell, respectively. The up-regulated CCGs in BLCA tumor tissues played important roles in immune cell infiltration and could be novel targets for tumor immunotherapy in BLCA.