Long Non-Coding RNA CASC9 Promotes Bladder Cancer Tumorigenicity and Metastasis <i>via</i> Modulating FZD6/Wnt/β-catenin Signaling Pathway

Abstract

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.