Bioinformatic Identification of Potential Hub Genes in Muscle-Invasive Bladder Urothelial Carcinoma

Abstract

Despite aggressive treatment approaches, muscle-invasive bladder urothelial carcinoma (MIBC) patients still have a 50% chance of developing general incurable metastases. Therefore, there is an urgent need for candidate markers to enhance diagnosis and generate effective treatments for this disease. We evaluated four mRNA microarray datasets to find differences between non-MIBC (NMIBC) and MIBC tissues. Through a gene expression profile analysis via the Gene Expression Omnibus database, we identified 56 differentially expressed genes (DEGs). Enrichment analysis of gene ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome pathways revealed the interactions between these DEGs. Next, we established a protein-protein interaction network to determine the interrelationship between the DEGs and selected 10 hub genes accordingly. Bladder urothelial carcinoma (BLCA) patients with COL1A2, COL5A1, and COL5A2 alterations showed poor disease-free survival rates, while BLCA patients with COL1A1 and LUM alterations showed poor overall survival rates. Oncomine analysis of MIBC versus NMIBC tissues showed that COL1A1, COL5A2, COL1A2, and COL3A1 were consistently among the top 20 overexpressed genes in different studies. Using the TCGAportal, we noted that the high expression of each of the four genes led to shorter BLCA patient overall survival. It was evident that BLCA patients with an elevated high combined gene expression had significantly shorter overall survival and relapse-free survival than those with low combined gene expression using PROGgeneV2. Using Gene Expression Profiling Interactive Analysis, we noted that COL1A1, COL1A2, COL3A1, and COL5A2 were positively correlated with each other in BLCA. These genes are considered as clinically relevant genes, suggesting that they may play an important role in the carcinogenesis, development, invasion, and metastasis of MIBC. However, considering we adopted a bioinformatic approach, more research is crucial to confirm our results. Nonetheless, our findings may have important prospective clinical implementations.

Identification of Prognostic Biomarkers of Potential Hub Genes in Urothelial Carcinoma and Function in Microenvironment

“…While Su et al indicated that let-7d can at least partially inhibit growth, metastasis, and tumor macrophage in ltration in renal cell carcinoma by targeting COL3A1 and CCL7 [42]. Yuan et al discovered that COL3A1 played certain roles in the progression of human UC and in uenced the prognosis probably by regulating MAPK signaling pathway, which contributed to the poor prognosis of UC [42]. These were consistent with our results.…”

“…These were consistent with our results. In a previous study, the in situ expression of COL5A2 increased in invasive breast cancer and was associated with ECM remodeling, suggesting that COL5A2 is associated with tumor progression in breast cancer [42]. Moreover, the expression of COL5A2 was related to the malignancy of colorectal cancer, suggesting its potential as a biomarker for colorectal cancer.…”

“…This is related to EMT, revealing the inhibitory effect of miR-25 on diffuse gastric cancer [15]. Notably, COL1A2 was highly expressed in pancreatic cancer, sarcoma, and gastric cancer tissues and promoted cell proliferation, migration, and invasion, which provided insights for mechanistic studies and clinical trials [42]. It has been reported that mRNA transcription level of bladder cancer is increased and CpG hypermethylation of COL1A2 contributes to proliferation and migration activity of human bladder cancer [43].…”

“…It has been reported that mRNA transcription level of bladder cancer is increased and CpG hypermethylation of COL1A2 contributes to proliferation and migration activity of human bladder cancer. Qiu et al reported that miR-29a/b promoted cell migration and invasion in nasopharyngeal carcinoma progression by regulating COL3A1 gene expression [42]. While Su et al indicated that let-7d can at least partially inhibit growth, metastasis, and tumor macrophage in ltration in renal cell carcinoma by targeting COL3A1 and CCL7 [42].…”

“…Qiu et al reported that miR-29a/b promoted cell migration and invasion in nasopharyngeal carcinoma progression by regulating COL3A1 gene expression [42]. While Su et al indicated that let-7d can at least partially inhibit growth, metastasis, and tumor macrophage in ltration in renal cell carcinoma by targeting COL3A1 and CCL7 [42]. Yuan et al discovered that COL3A1 played certain roles in the progression of human UC and in uenced the prognosis probably by regulating MAPK signaling pathway, which contributed to the poor prognosis of UC [42].…”