Abstract
BackgroundMuscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice.MethodsThis study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways.ResultsIn the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC.ConclusionsIn summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.
Highlights
Muscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide
Based on the prognostic stratification, we investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of MIBC progression and provide new therapeutic approaches for these high-risk patients
Previous studies [23, 24] have reported that TNS1 could increase the metastatic potential and alter expression of genes involved in cell motility in colorectal cancer, and may be a potential prognostic biomarker in human colorectal cancer. These results indicated that KLK6 and TRIM56 may be associated with worse prognosis of MIBC via regulating cell–cell communication and mismatch repair (MMR), respectively
Summary
Muscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. With the genomewide gene expression data, several studies have identified a combination of gene signatures to predict the prognosis of MIBC. The novel combination markers of USP18 and DGCR2 can predict survival in patients with muscle invasive bladder cancer [9]. NR1H3 expression is identified as a prognostic factor of overall survival for patients with muscle-invasive bladder cancer [10]. To avoid these limitations, we attempted to detect a combination of gene signatures for MIBC prognostic prediction and stratification. Based on the prognostic stratification, we investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of MIBC progression and provide new therapeutic approaches for these high-risk patients
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