Activation of Piezo1 contributes to matrix stiffness‐induced angiogenesis in hepatocellular carcinoma

作者：Miao Li, Xi Zhang, Mimi Wang, Yaohui Wang, Jiali Qian, Xiaoxia Xing, Zhiming Wang, Yang You, Kun Guo, Jie Chen, Dongmei Gao, Yan Zhao, Lan Zhang, Rongxin Chen, Jiefeng Cui, Zhenggang Ren · 发表于：癌症：英文版 · 年份：2022 · DOI：10.1002/cac2.12364 · 被引用次数：175 · 研究领域：Erythrocyte Function and Pathophysiology、Phagocytosis and Immune Regulation、Blood properties and coagulation

Abstract Background Despite integrin being highlighted as a stiffness‐sensor molecule in matrix stiffness‐driven angiogenesis, other stiffness‐sensor molecules and their mechanosensory pathways related to angiogenesis in hepatocellular carcinoma (HCC) remain obscure. Here, we explored the interplay between Piezo1 and integrin β1 in the mechanosensory pathway and their effects on HCC angiogenesis to better understand matrix stiffness‐induced angiogenesis. Methods The role of Piezo1 in matrix stiffness‐induced angiogenesis was investigated using orthotopic liver cancer SD rat models with high liver stiffness background, and its clinical significance was evaluated in human HCC tissues. Matrix stiffness‐mediated Piezo1 upregulation and activation were assayed using an in vitro fibronectin (FN)‐coated cell culture system with different stiffness, Western blotting and Ca 2+ probe. The effects of shPiezo1‐conditioned medium (CM) on angiogenesis were examined by tube formation assay, wound healing assay and angiogenesis array. The underlying mechanism by which Piezo1 participated in matrix stiffness‐induced angiogenesis was analyzed by microRNA quantitative real‐time polymerase chain reaction (qRT‐PCR), matrix stiffness measurement, dual‐luciferase reporter assay, ubiquitination assay and co‐immunoprecipitation. Results Increased matrix stiffness significantly upregulated Piezo1 expression at both cellular and tissue levels, and high expression of Piezo1 indicated an unfavorable prog...