Long non-coding RNA CASC9 promotes tumor growth and metastasis via modulating FZD6/Wnt/\u03b2-catenin signaling pathway in bladder cancer

Yonghao Zhan,Jianguo Wen,Yuchen Liu,Xuepei Zhang,Shuanbao Yu,Lianghao Zhang

doi:10.1186/s13046-020-01624-9

Abstract

BackgroundAccumulating 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.MethodsComprehensive 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.ResultsThis 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.ConclusionIn 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.

Highlights

Accumulating evidence have highlighted the importance of long noncoding RNAs in multiple cancers development and progression
Cancer susceptibility candidate 9 (CASC9) expression is up-regulated in Bladder cancer (BC) We conducted comprehensive Long non-coding RNA (lncRNA) expression profile analyses using The Cancer Genome Atlas (TCGA)-BLCA dataset and a Gene Expression Omnibus (GEO) detaset (GSE89006) to identify lncRNAs profile alterations and uncover valuable lncRNA candidates for BC and explored their clinical relevance
We found CASC9 expression were up-regulated in TCGA-BLCA (Fig. 1a and Fig. S1A) and GSE89006 (Fig. 1b and Fig. S1B) datasets and higher CASC9 expression was associated with BC patients’ shorter Disease free survival (DFS) (Fig. 1c) in TCGA-BLCA dataset

Summary

Introduction

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 noncoding RNA and plays important regulatory role in diverse biological processes of cancers. A growing number of evidence has showed that many lncRNAs play important regulatory roles in diverse biological processes of BC, such as BLACAT2, LNMAT1, LNMAT2, PTENP1, UCA-1, HOTAIR, and etc. CASC9 forms a complex with HNRNPL and coregulates target genes expression and subsequently activates AKT-signaling pathway, in hepatocellular carcinoma. CASC9 activates LAMC2 expression through altering LAMC2 promoter H3K27me level by recruits CBP and subsequently promotes esophageal squamous cell carcinoma metastasis. CASC9 recruiting EZH2 to PDCD4 promoter and alters H3K27me level and subsequently promotes esophageal squamous cell carcinoma metastasis by activating PDCD4 expression [24]. The biological function and underlying mechanism of action of CASC9 in BC is completely unknown

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Conclusion