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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2023

Open Access 01-12-2023 | Metastasis | Research

ZEB1-mediated biogenesis of circNIPBL sustains the metastasis of bladder cancer via Wnt/β-catenin pathway

Authors: Yuanlong Li, Yao Kong, Mingjie An, Yuming Luo, Hanhao Zheng, Yan Lin, Jiancheng Chen, Jin Yang, Libo Liu, Baoming Luo, Jian Huang, Tianxin Lin, Changhao Chen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2023

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Abstract

Background

Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored.

Methods

RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues.

Results

In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2–9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression.

Conclusions

Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients.

Graphical Abstract

Appendix
Available only for authorised users
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Metadata
Title
ZEB1-mediated biogenesis of circNIPBL sustains the metastasis of bladder cancer via Wnt/β-catenin pathway
Authors
Yuanlong Li
Yao Kong
Mingjie An
Yuming Luo
Hanhao Zheng
Yan Lin
Jiancheng Chen
Jin Yang
Libo Liu
Baoming Luo
Jian Huang
Tianxin Lin
Changhao Chen
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Metastasis
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2023
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-023-02757-3

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