Abstract
Human bladder cancer (BCa) is the most common urogenital system malignancy. Patients with BCa have limited treatment efficacy in clinical practice. Novel biomarkers could provide more crucial information conferring to cancer diagnosis, treatment, and prognosis. Here, we aimed to explore and identify novel biomarkers associated with cancer-specific survival of patients with BCa to build a prognostic signature. Based on univariate Cox regression, Lasso regression, and multivariate Cox regression analysis, we conducted an integrated analysis in the training set (GSE32894) and established a six-gene signature to predict the cancer-specific survival for human BCa. The six genes were Cyclin Dependent Kinase 4 (CDK4), E2F Transcription Factor 7 (E2F7), Collagen Type XI Alpha 1 Chain (COL11A1), Bradykinin Receptor B2 (BDKRB2), Yip1 Interacting Factor Homolog B (YIF1B), and Zinc Finger Protein 415 (ZNF415). Then, we validated the prognostic value of the model by using two other datasets (GSE13507 and TCGA). Also, we conducted univariate and multivariate Cox regression analyses, and results indicated that the six-gene signature was an independent prognostic factor of cancer-specific survival of patients with BCa. Functional analysis was performed based on the differentially expressed genes of low- and high-risk patients, and we found that they were enriched in lipid metabolic and cell division-related biological processes. Meanwhile, the gene set enrichment analysis (GSEA) revealed that high-risk samples were enriched in cell cycle and cancer-related pathways [G2/M checkpoint, E2F targets, mitotic spindle, mTOR signaling, spermatogenesis, epithelial–mesenchymal transition (EMT), DNA repair, PI3K/AKT/mTOR signaling, unfolded protein response (UPR), and MYC targets V2]. Lastly, we detected the relative expression of each signature in BCa cell lines by quantitative real-time PCR (qRT-PCR). As far as we know, currently, the present study is the first research that developed and validated a cancer-specific survival prognostic index based on three independent cohorts. The results revealed that this six-gene signature has a predictive ability for cancer-specific prognosis. Moreover, we also verified the relative expression of these six signatures between the bladder cell line and four BCa cell lines by qRT-PCR. Nevertheless, experiments to further explore the function of six genes are lacking.
Highlights
Human bladder cancer (BCa) is the most common urogenital system malignancy, and among the cancers related to males, it ranks fourth (Siegel et al, 2013)
The result revealed that there were 60 genes significantly associated with prognosis (p < 1E-6), which were defined as prognostic genes
The candidate genes were performed by Least Absolute Shrinkage and Selection Operator (LASSO) regression (Figures 2A,B), and CDK4, GUCY1A2, NMMT, E2F7, ZNF415, HTR2A, NUAK1, COL11A1, THOP1, TNFRSF6B, BCAT1, CBX2, CTRC, DHRS2, BDKRB2, YIF1B, and SLC22A16 were screened
Summary
Human bladder cancer (BCa) is the most common urogenital system malignancy, and among the cancers related to males, it ranks fourth (Siegel et al, 2013). In China, BCa is one of the most common urologic malignancies, and in the past few years, the incidence and mortality rates have increased gradually (Chen et al, 2015). Bacillus Calmette Guerin installation remains the gold standard of NMIBC, while appropriately 40% of patients are not sensitive to it, even 15% of patients may progress into MIBC after treating it (Seidl, 2020). Most MIBCs were treated with radical cystectomy (Chen et al, 2015; Pang et al, 2016). It is essential to understand the critical biomarkers and key pathways governing tumor behavior for better treatment strategies and prediction of prognosis
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