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Background Accumulating evidence have highlighted the importance of long noncoding RNAs (lncRNAs) in multiple cancers development and progression. Cancer susceptibility candidate 9 (CASC9) is a novel long non-coding RNA and plays important regulatory role in diverse biological processes of cancers. However, the clinical significance and molecular mechanism of CASC9 in bladder cancer is still unknown. Methods Comprehensive lncRNAs profiling analysis were conducted to identify lncRNAs profile alterations and uncover valuable lncRNA candidates for bladder cancer. The expression level of CASC9 was determined in a total of 106 patients with bladder cancer. Loss-of-function experiments were performed to identify the functions of CASC9 in tumor growth and metastasis of bladder cancer in vitro and in vivo. Bioinformatics analysis and further experiments were performed to explore the molecular mechanisms underlying the functions of CASC9. Results This study found that CASC9 expression was markedly upregulated in bladder cancer and related to histological grade, TNM stage and prognosis. Knockdown of CASC9 inhibited tumor growth and metastasis of bladder cancer in vitro and in vivo. Mechanistically, we found that CASC9 functions as a miRNA sponge to positively regulate FZD6 expression and subsequently activates Wnt/β-catenin signaling pathway, thus playing an oncogenic role in bladder cancer pathogenesis. Conclusion In summary, lncRNA CASC9 plays a critical regulatory role in bladder cancer. The CASC9/miR-497-5p/ FZD6 axis provides insights for regulatory mechanism of bladder cancer, and new strategies for clinical practice.

BackgroundIdentify immune-related gene pairs (IRGPs) signature related to the prognosis and immunotherapeutic efficiency for bladder cancer (BLCA) patients.Materials and MethodsOne RNA-seq dataset (The Cancer Genome Atlas Program) and two microarray datasets (GSE13507 and GSE31684) were included in this study. We defined these cohorts as training set to construct IRGPs and one immunotherapy microarray dataset as validation set. Identifying BLCA subclasses based on IRGPs by consensus clustering. The Lasso penalized Cox proportional hazards regression model was used to construct prognostic signature and potential molecular mechanisms were analyzed.ResultsThis signature can accurately predict the overall survival of BLCA patients and was verified in the immunotherapy validation set. IRGP-signatures can be used as independent prognostic risk factor in various clinical subgroups. Use the CIBERSORT algorithm to assess the abundance of infiltrating immune cells in each sample, and combine the results of the gene set enrichment analysis of a single sample to explore the differences in the immune microenvironment between IRPG signature groups. According to the results of GSVA, GSEA, and CIBERSORT algorithm, we found that IRGP is strikingly positive correlated with tumor microenvironment (TME) stromal cells infiltration, indicating that the poor prognosis and immunotherapy might be caused partly by enrichment of stromal cells. Finally, the results from the TIDE analysis revealed that IRGP could efficiently predict the response of immunotherapy in BLCA.ConclusionThe novel IRGP signature has a significant prognostic value for BLCA patients might facilitate personalized for immunotherapy.

Background: Accumulating evidence have highlighted the importance of long noncoding RNAs (lncRNAs) in multiple cancers development and progression. Cancer susceptibility candidate 9 (CASC9) is a novel long non-coding RNA and plays important regulatory role in diverse biological processes of cancers. However, the clinical significance and molecular mechanism of CASC9 in bladder cancer is still unknown. Methods: Comprehensive lncRNAs profiling analysis were conducted to identify lncRNAs profile alterations and uncover valuable lncRNA candidates for bladder cancer. The expression level of CASC9 was determined in a total of 106 patients with bladder cancer. Loss-of-function experiments were performed to identify the functions of CASC9 in tumor growth and metastasis of bladder cancer in vitro and in vivo. Bioinformatics analysis and further experiments were performed to explore the molecular mechanisms underlying the functions of CASC9. Findings: This study found that CASC9 expression was markedly upregulated in bladder cancer and related to histological grade, TNM stage and prognosis. Knockdown of CASC9 inhibited tumor growth and metastasis of bladder cancer in vitro and in vivo. Mechanistically, we found that CASC9 functions as a miRNA sponge to positively regulate FZD6 expression and subsequently activates Wnt/β-catenin signaling pathway, thus playing an oncogenic role in bladder cancer pathogenesis. Interpretation: In summary, lncRNA CASC9 plays a critical regulatory role in bladder cancer. The CASC9/miR-497-5p/ FZD6 axis provides insights for regulatory mechanism of bladder cancer, and new strategies for clinical practice. Funding Statement: This work was supported by National Natural Science Foundation of China [81773257, 81972867, 81672546], China Postdoctoral Science Foundation [2019M662544], Natural Science Foundation of Guangdong (2018B030306023) and the Shenzhen Municipal Government of China (JCYJ20180507184642475). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of The First Affiliated Hospital of Zhengzhou University and Peking University First Hospital (Beijing, China) and conducted in accordance with its recommendations and ethical regulations.

Background Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are potential biomarkers and key regulators of tumour development and progression. SOX2 overlapping transcript (SOX2OT) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancer and cancer stem cells. However, the clinical significance and molecular mechanism of SOX2OT in bladder cancer are still unknown. Methods The expression level of SOX2OT was determined by RT-qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell (BCC) lines. Bladder cancer stem cells (BCSCs) were isolated from BCCs using flow cytometry based on the stem cell markers CD44 and ALDH1. Loss-of-function experiments were performed to investigate the biological roles of SOX2OT in the stemness phenotype of BCSCs. Comprehensive transcriptional analysis, RNA FISH, dual-luciferase reporter assays and western blots were performed to explore the molecular mechanisms underlying the functions of SOX2OT. Results SOX2OT was highly expressed in bladder cancer, and increased SOX2OT expression was positively correlated with a high histological grade, advanced TNM stage and poor prognosis. Further experiments demonstrated that knockdown of SOX2OT inhibited the stemness phenotype of BCSCs. Moreover, inhibition of SOX2OT delayed xenograft tumour growth and decreased metastases in vivo. Mechanistically, we found that SOX2OT was mainly distributed in the cytoplasm and positively regulated SOX2 expression by sponging miR-200c. Furthermore, SOX2 overexpression reversed the SOX2OT silencing-induced inhibition of the BCSC stemness phenotype. Conclusion This study is the first to demonstrate that SOX2OT plays an important regulatory role in BCSCs and that SOX2OT may serve as a potential diagnostic biomarker and therapeutic target in bladder cancer.

Supplemental Digital Content is available in the text, Background: Accumulating emerging studies have demonstrated that systemic inflammation can obviously affect tumor occurrence and progression. Nevertheless, the prognostic value of hematological inflammation biomarkers in bladder cancer is controversial. Thus, we conducted a meta-analysis to evaluate the key hematological biomarkers with various clinical outcomes in bladder cancer. Methods: We used online databases PUBMED and EMBASE to search relevant studies published prior to August 2019. After collecting the basic characteristics and prognostic data from the studies included, overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) were used as primary results. Subgroup analyses were performed according to ethnicity, the number of samples, survival outcomes, the value of cut-off, follow-up time and metastasis stage. Results: Thirty-three independent studies with 17,087 bladder cancer patients were added in the present analysis. The collected results showed that the increased neutrophil-to-lymphocyte ratio was associated with a poor OS (hazard ratio [HR] = 1.48, 95% confidence interval [CI]: 1.32–1.67, P