Ma Minghai, Li Jianpeng, Li Xing, Jing Minxuan, Wang Lu, Jiang Yunzhong, Yang Zezhong, He Jiale, Wang Min, Liu Hang, Chen Yutong, Mi Kaibo, Wang Lei, Fan Jinhai, Du Hongxia
Department of Pharmacology and Toxicology, School of Basic Medical Sciences, Xi'an Medical University, Xi'an, China.
Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
Cancer Med. 2025 Jul;14(14):e71059. doi: 10.1002/cam4.71059.
Emerging evidence implicates mechanotransduction pathways in modulating bladder carcinoma (BLCA) pathogenesis. However, the crosstalk between Piezo1 and integrin β1 (ITGB1) in extracellular matrix (ECM) stiffness-driven tumorigenesis remains a critical knowledge gap. This study systematically investigates the functional synergy of Piezo1/ITGB1 in orchestrating ECM biomechanical remodeling to fuel BLCA progression.
Utilizing an integrative framework combining clinical histopathology, in vivo tumor models, multiomics profiling, molecular biology experiments, matrix stiffness quantification, calcium flux analysis, and YAP signaling interrogation, we dissected the mechanochemical interplay between Piezo1/ITGB1 activation and ECM dynamics.
Clinical and animal data revealed that Piezo1/ITGB1 coactivation was strongly correlated with ECM stiffness-induced BLCA proliferation and poor clinical prognosis. The coordinated expression of Piezo1/ITGB1 enhanced ECM interaction, organization, adhesion, and collagen binding. Crucially, Piezo1/ITGB1 overexpression promoted cancer development by suppressing apoptosis and enhancing proliferation. Mechanistically, ECM stiffness triggered Piezo1/ITGB1-dependent Ca influx, which facilitated YAP nuclear translocation and subsequent upregulation of downstream targets CTGF, α-SMA, and COL1A1, thereby reinforcing collagen deposition and matrix stiffening.
Our work uncovers a feedforward mechano-oncogenic axis wherein Piezo1/ITGB1 cooperativity converts ECM cues into sustained protumorigenic signaling through Ca/YAP-mediated transcriptional reprogramming. This paradigm redefines ECM stiffness not merely as a pathological consequence but as an active driver of BLCA progression, proposing precision targeting of the Piezo1/ITGB1 triad as a mechanotherapy strategy.
新出现的证据表明机械转导通路在调节膀胱癌（BLCA）发病机制中起作用。然而，在细胞外基质（ECM）硬度驱动的肿瘤发生过程中，Piezo1与整合素β1（ITGB1）之间的相互作用仍是一个关键的知识空白。本研究系统地研究了Piezo1/ITGB1在协调ECM生物力学重塑以促进BLCA进展中的功能协同作用。
利用结合临床组织病理学、体内肿瘤模型、多组学分析、分子生物学实验、基质硬度定量、钙流分析和YAP信号询问的综合框架，我们剖析了Piezo1/ITGB1激活与ECM动态之间的机械化学相互作用。
临床和动物数据显示，Piezo1/ITGB1共激活与ECM硬度诱导的BLCA增殖和不良临床预后密切相关。Piezo1/ITGB1的协同表达增强了ECM相互作用、组织、粘附和胶原结合。至关重要的是，Piezo1/ITGB1过表达通过抑制细胞凋亡和增强增殖促进癌症发展。机制上，ECM硬度触发Piezo1/ITGB1依赖性钙内流，促进YAP核转位并随后上调下游靶点CTGF、α-SMA和COL1A1，从而加强胶原沉积和基质硬化。
我们的工作揭示了一个前馈机械致癌轴，其中Piezo1/ITGB1协同作用通过Ca/YAP介导的转录重编程将ECM信号转化为持续的促肿瘤信号。这一模式重新定义了ECM硬度不仅是一种病理结果，而且是BLCA进展的积极驱动因素，提出将Piezo1/ITGB1三联体作为一种机械治疗策略进行精准靶向。
