Background In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear. Methods Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses. Results ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/β-catenin pathway. Conclusions This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.

Background: Sphingosine kinase 1 (SPHK1) is a key enzyme that catalyzes the phosphorylation of sphingosine. Recent studies reported SPHK1 to be associated with renal cell carcinoma (RCC) progression by inducing targeted therapy resistance. However, the expression and the clinical significance of SPHK1 on RCC in those having received targeted therapy have not been elucidated. The present study explored the expression of SPHK1 in RCC tissues from targeted therapy recipients, the correlation of SPHK1 with clinicopathological parameters, and the effect of SPHK1 on RCC patient prognosis.Methods: Differential gene expression analysis of RCC treated with and without targeted therapy was performed. The correlations of SPHK1 expression with clinical parameters of RCC were examined. Gene set enrichment analysis (GSEA) was performed to clarify the potential role of SPHK1 associated with targeted therapy resistance. The value of SPHK1 as a diagnostic marker for RCC was also evaluated. The Kaplan-Meier method was applied to analyze the correlation between SPHK1 expression and patient survival rate by using the clinical data from patients with RCC.Results: Significant overexpression of SPHK1 was detected in RCC treated with targeted therapy. SPHK1 expression was closely correlated with RCC progression-related clinicopathological parameters. Therefore, elevated SPHK1 could effectively diagnose RCC and distinguish RCC with an advanced clinical stage and a high pathological grade. SPHK1 was associated with the stemness of RCC cells via the activation of the Wnt, Hedgehog, or Notch signaling pathways in targeted drug-treated or untreated RCC. Survival analysis of a large cohort of RCC samples indicated overexpression of SPHK1 to be inversely correlated with the overall and disease-free survival of patients with RCC.Conclusions: Our study indicated that SPHK1 associated with targeted therapy resistance could serve as a potential prognostic marker and a valuable biomarker of response to angiogenic agents in RCC.

Background: Immunotherapy has been proved to be effective for bladder cancer (BLCA). However, the molecular network involved in BLCA tumor immune response remains unclear. This study aims to construct an immune-related ceRNA network and to identify the prognostic value. Methods: Based on The Cancer Genome Atlas (TCGA), we used single-sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA) to determine immune-related mRNA, lncRNA and miRNA. Then least absolute shrinkage, and selection operator (LASSO) and Cox regression were performed to identify the mRNAs with high prognostic value, and accordingly, the risk score was calculated. Internal and external validation were performed both in TCGA and GSE13507 with Kaplan-Meier (KM) survival and Receiver Operating Characteristic (ROC) curve analysis. Using the immune-related mRNA, lncRNA and miRNA, a ceRNA network was established via MiRcode, starBase, miRDB, miRTarBase and TargetScan. Besides, we also explore the relationship between the risk score and immune cell infiltration via CIBERSORT algorithm. Results: 5 mRNAs (PCGF3, FASN, DPYSL2, TGFBI and NTF3) were ultimately identified, and KM survival analysis displayed the 5-mRNA risk signature could predict the prognosis of BLCA with high efficacy both in TCGA (p = 1.006e-13) and GSE13507 (p = 7.759e-04). Using miRNA targeting molecular prediction database, an immune-related ceRNA network, including 5 mRNAs, 24 miRNAs and 86 lncRNAs, was constructed. Memory B cells, activated dendritic cells, and regulatory T cells infiltration into tumors were negatively correlated with risk score, while the infiltration levels of macrophages M0, M1 and M2 were positively correlated with risk score. Conclusion: This study helped to better understand the molecular mechanisms of tumor immune response from the view of ceRNA hypothesis, and provided a novel prognostic signature for bladder cancer.

Background In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear. Methods Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses. Results ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/β-catenin pathway. Conclusions This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.