Li Yi-Ming, Xu Cong, Sun Bo, Zhong Fang-Jing, Cao Momo, Yang Lian-Yue
Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, Hunan, China.
Cancer Cell Int. 2022 Apr 23;22(1):162. doi: 10.1186/s12935-022-02574-2.
Piezo1 has been revealed to play a regulatory role in vascular development and progression of variety tumors. However, whether and how the progression of hepatocellular carcinoma (HCC) regulated by Piezo1 remains elusive. This study aimed to elucidate the effect and mechanisms of Piezo1 in HCC.
The mRNA and protein expression level of Piezo1 in HCC samples and cell lines was determined by qRT-PCR, western blot and immunohistochemistry analyses. Two independent study cohorts containing 280 patients were analyzed to reveal the association between Piezo1 expression and clinicopathological characteristics. Series of in vitro and in vivo experiments were used to validate the function of Piezo1 in HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. Immunoprecipitation, immunofluorescence and in vitro and in vivo experiments were used to explore the molecular mechanism of Piezo1 in HCC progression.
Our results demonstrated the Piezo1 expression was significantly upregulated in HCC tissues and cell lines, and upregulation of Piezo1 closely correlated with aggressive clinicopathological features and poor prognosis. Knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly restrained proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, metastasis, EMT in vivo. TGF-β signaling pathway was most significant enriched pathway in GSEA. Finally, tumor promotion effect of Piezo1 was found to exerted through recruiting and combining Rab5c to activating TGF-β signaling pathway.
Piezo1 significantly related to poor prognosis and promotes progression of hepatocellular carcinoma via activating TGF-β signaling, which suggesting that Piezo1 may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.
Piezo1已被揭示在血管发育和多种肿瘤进展中发挥调节作用。然而，Piezo1是否以及如何调节肝细胞癌（HCC）的进展仍不清楚。本研究旨在阐明Piezo1在HCC中的作用及机制。
通过qRT-PCR、蛋白质免疫印迹和免疫组织化学分析测定Piezo1在HCC样本和细胞系中的mRNA和蛋白质表达水平。分析两个包含280例患者的独立研究队列，以揭示Piezo1表达与临床病理特征之间的关联。采用一系列体外和体内实验验证Piezo1在HCC中的功能。进行基因集富集分析（GSEA）以探索Piezo1的信号通路。采用免疫沉淀、免疫荧光以及体外和体内实验来探索Piezo1在HCC进展中的分子机制。
我们的结果表明，Piezo1在HCC组织和细胞系中表达显著上调，且Piezo1的上调与侵袭性临床病理特征和不良预后密切相关。敲低HCCLM3和Hep3B细胞中的Piezo1可显著抑制体外HCC细胞的增殖、迁移、侵袭和上皮-间质转化（EMT），以及体内肿瘤生长、转移和EMT。TGF-β信号通路是GSEA中最显著富集的通路。最后，发现Piezo1的肿瘤促进作用是通过招募并结合Rab5c激活TGF-β信号通路来实现的。
Piezo1与不良预后显著相关，并通过激活TGF-β信号促进肝细胞癌进展，这表明Piezo1可能作为一种新的预后预测指标及HCC患者潜在的治疗靶点。
