CircFSCN1 induces tumor progression and triggers epithelial–mesenchymal transition in bladder cancer through augmentation of MDM2-mediated p53 silencing

• Published in: Cellular signalling Vol. 114; p. 110982
• Main Authors: Deng, Wen, Chen, Ru, Xiong, Situ, Nie, Jianqiang, Yang, Hailang, Jiang, Ming, Hu, Bing, Liu, Xiaoqiang, Fu, Bin
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-02-2024
• Subjects: Bladder cancer; Carrier Proteins - metabolism; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; circFSCN1; Epithelial-Mesenchymal Transition - genetics; Epithelial–mesenchymal transition; Gene Expression Regulation, Neoplastic; Humans; MDM2; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; miR-145-5p; p53; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; RNA, Circular - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; MDM2; Epithelial–mesenchymal transition; circFSCN1; Bladder cancer; miR-145-5p; p53
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2023.110982

Compelling evidences indicated that circular RNA (circRNA) was a novel class of non-coding RNA that played critical and distinct roles in various human cancers. Their roles and underlying mechanisms, however, in bladder cancer (BC) remained largely unknown.
A novel circRNA derived from oncogene FSCN1, namely circFSCN1, was selected from a microarray analysis. The phenotypic alterations were assessed with functional experiments in vitro and in vivo. RNA immunoprecipitation, RNA pull-down, luciferase reporter assay, and rescue experiments were sequentially proceeded to clarify the interactions among circFSCN1, miR-145-5p, MDM2, and p53.
We observed that the expression of circFSCN1 was elevated in BC cell lines and tissues. Next, we validated the fundamental properties of circFSCN1. In the meanwhile, we noticed that elevated circFSCN1 level, pathological T stage, and tumor grade were identified as independent factors associated with cancer-specific survivals of patients with BC，as determined by univariate and multivariable COX regression analyses. Phenotype studies demonstrated the promoting effects of circFSCN1 on the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of BC cells. Mechanistically, we elucidated that circFSCN1, primarily localized in the cytoplasm, upregulated the expression of MDM2, a well-known inhibitor of p53, by directly binding to miR-145-5p.
Elevated circFSCN1 induces tumor progression and EMT in BC via enhancing MDM2-mediated silencing of p53 by sponging miR-145-5p. Targeting circFSCN1, a novel identified target, may be conducive in impeding BC progression and providing survival benefits for patients with BC.
•CircFSCN1 was independently related to cancer-specific survivals of patients with bladder cancer.•CircFSCN1 promoted the development and epithelial–mesenchymal transition of bladder cancer.•CircFSCN1 was primarily localized in the cytoplasm.•CircFSCN1 induced bladder cancer progression via miR-145-5p-MDM2-p53 axis.