循环RNA (circRNAs) 以前mRNA 的背 splicing 形成环状，在膀胱癌 (BCa) 中广泛表达并影响增殖、侵袭和转移。然而，调节BCa 远处转移的circRNA 生物发生机制仍未被探索。通过运用BCa 与正常邻近组织之间的RNA测序数据来鉴定差异表达的circRNA。通过一系列的生化实验来研究circNIPBL 在BCa中的功能。在一组更大的BCa组织上检测circNIPBL的临床意义。本研究中，我们鉴定出了一个新的circRNA (hsa_circ_0001472)，circNIPBL，在BCa患者中显著上调，并且对患者的不良预后有巨大影响。在功能上，circNIPBL在体内和体外促进了BCa的转移。机制上，通过直接结合miR-16-2-3p来上调Wnt5a的表达，从而激活了Wnt/β-catenin信号通路，进一步上调了ZEB1的表达，并引发了BCa的EMT。此外，我们揭示了ZEB1与NIPBL前mRNA的2-9外显子的内侧内含子相互作用，以触发circNIPBL的生物发生，形成了正反馈环。重要的是，circNIPBL的过表达显著促进BCa的远处转移，在正位膀胱癌模型中，而沉默ZEB1显著阻断了circNIPBL过表达引起的转移效应。我们的研究凸显了circNIPBL诱导的Wnt信号通路激活引发了ZEB1介导的circNIPBL生物发生，通过circNIPBL/miR-16-2-3p/Wnt5a/ZEB1轴形成了一个正反馈环，支持circNIPBL作为BCa患者的新型治疗靶点和潜在生物标志物。©2023. 作者。

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.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.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.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.© 2023. The Author(s).