Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
Cell Calcium. 2021 May;95:102367. doi: 10.1016/j.ceca.2021.102367. Epub 2021 Feb 13.
Accumulating evidence has revealed the mechanosensitive ion channel protein Piezo1 is contributing to tumorigenesis. However, its role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we demonstrated that Piezo1 was expressed in the HepG2 cell line and depletion of Piezo1 impaired proliferation and migration, as well as increased apoptosis in these cells. Using a Piezo1-specific activator, Yoda1, we identified that calcium entry induced by Yoda1 resulted in phosphorylation of JNK, p38, and ERK, thereby activating the mitogen-activated protein kinase (MAPK) pathway, in a dose- and time-dependent manner. More strikingly, Piezo1 activation integrated with YAP signaling to control the nuclear translocation of YAP and regulation of its target genes. JNK, p38, and ERK (MAPK signaling) regulated Yoda1-induced YAP activation. Consistent with the association of calpain with Piezo1, we also found that calpain activity was decreased by siRNA-mediated knockdown of Piezo1. In addition, the growth of HCC tumors was inhibited in Piezo1 haploinsufficient mice. Together, our findings establish that the Piezo1/MAPK/YAP signaling cascade is essential for HepG2 cell function. These results highlight the importance of Piezo1 in HCC and the potential utility of Piezo1 as a biomarker and therapeutic target.
越来越多的证据表明，机械敏感离子通道蛋白 Piezo1 参与了肿瘤的发生。然而，其在肝细胞癌（HCC）中的作用仍未被探索。在本研究中，我们证明 Piezo1 在 HepG2 细胞系中表达，Piezo1 的缺失会损害这些细胞的增殖和迁移能力，并增加细胞凋亡。使用 Piezo1 特异性激活剂 Yoda1，我们发现 Yoda1 诱导的钙内流导致 JNK、p38 和 ERK 的磷酸化，从而以剂量和时间依赖的方式激活丝裂原活化蛋白激酶（MAPK）通路。更引人注目的是，Piezo1 的激活与 YAP 信号整合，控制 YAP 的核转位及其靶基因的调控。JNK、p38 和 ERK（MAPK 信号）调节 Yoda1 诱导的 YAP 激活。与 Piezo1 与钙蛋白酶的关联一致，我们还发现 Piezo1 的 siRNA 介导敲低降低了钙蛋白酶的活性。此外，Piezo1 杂合不足小鼠的 HCC 肿瘤生长受到抑制。总之，我们的研究结果表明，Piezo1/MAPK/YAP 信号级联对于 HepG2 细胞的功能至关重要。这些结果强调了 Piezo1 在 HCC 中的重要性，以及 Piezo1 作为生物标志物和治疗靶点的潜在用途。
