Abstract
Long non-coding RNAs (lncRNAs) act as competing endogenous RNAs (ceRNAs) to regulate mRNA expression through sponging microRNA in tumorigenesis and progression. However, following the discovery of new RNA interaction, the differentially expressed RNAs and ceRNA regulatory network are required to update. Our study comprehensively analyzed the differentially expressed RNA and corresponding ceRNA network and thus constructed a potentially predictive tool for prognosis. “DESeq2” was used to perform differential expression analysis. Two hundred and six differentially expressed (DE) lncRNAs, 222 DE miRNAs, and 2,463 DE mRNAs were found in this study. The lncRNA-mRNA interactions in the miRcode database and the miRNA-mRNA interactions in the starBase, miRcode, and mirTarBase databases were searched, and a competing endogenous RNA (ceRNA) network with 186 nodes and 836 interactions was subsequently constructed. Aberrant expression patterns of lncRNA NR2F1-AS1 and lncRNA AC010168.2 were evaluated in two datasets (GSE89006, GSE31684), and real-time polymerase chain reaction was also performed to validate the expression pattern. Furthermore, we found that these two lncRNAs were independent prognostic biomarkers to generate a prognostic lncRNA signature by univariate and multivariate Cox analyses. According to the lncRNA signature, patients in the high-risk group were associated with a poor prognosis and validated by an external dataset. A novel genomic-clinicopathologic nomogram to improve prognosis prediction of bladder cancer was further plotted and calibrated. Our study deepens the understanding of the regulatory ceRNA network and provides an easy-to-do genomic-clinicopathological nomogram to predict the prognosis in patients with bladder cancer.
Highlights
Bladder cancer (BC) is the most common urological cancer and the major cause of cancer-related death globally, contributing to 165,100 deaths per year and resulting in significant morbidity and mortality [1]
We found that Long non-coding RNAs (lncRNAs) NR2F1-AS1 and lncRNA AC010168.2 were independent prognostic biomarkers and used for constructing a lncRNA signature to predict the prognosis of bladder cancer
Based on miRcode database for lncRNA-miRNA interactions and starBase, miRcode, and mirTarBase databases for mRNA-miRNA interactions, 60 DElncRNA (44 upregulated lncRNA and 16 downregulated lncRNA), 66 DEmiRNA (42 upregulated miRNAs and 24 downregulated miRNA), and 60 DEmRNA (12 upregulated mRNA and 48 downregulated mRNA) were obtained as nodes, and 836 interactions were displayed as edges
Summary
Bladder cancer (BC) is the most common urological cancer and the major cause of cancer-related death globally, contributing to 165,100 deaths per year and resulting in significant morbidity and mortality [1]. A large proportion of bladder cancer is non-muscle invasive bladder cancer (NMIBC) presenting at the first diagnosis, the risk of recurrence is nearly 30%, requiring a second transurethral resection of bladder tumor [3]. Radical cystectomy after neoadjuvant chemotherapy is a standard treatment for muscle invasive bladder cancer. The 5year overall survival rate is low (38.6%) among cT3-4aN0 patients after neoadjuvant chemotherapy and radical cystectomy [5]. Great progress has been made in the field of immunotherapy by PD-1/PD-L1 inhibitors, which are approved for treating patients with metastatic urothelial carcinoma. The effective options for treating patients with metastatic bladder cancer are extremely limited and required. It is of great importance to investigate the molecular mechanisms underlying bladder cancer progression, and discover new molecular biomarkers of diagnosis and prognosis for patients with bladder cancer [7]
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