College of Bioengineering, Chongqing University, Chongqing 400030, China.
Int J Mol Sci. 2022 May 10;23(10):5342. doi: 10.3390/ijms23105342.
Alteration of liver tissue mechanical microenvironment is proven to be a key factor for causing hepatocyte injury and even triggering the occurrence of hepatocellular carcinoma; however, the underlying mechanisms involved are not fully understood. In this study, using a customized, pressure-loading device, we assess the effect of pressure loading on DNA damage in human hepatocytes. We show that pressure loading leads to DNA damage and S-phase arresting in the cell cycle, and activates the DNA damage response in hepatocytes. Meanwhile, pressure loading upregulates Dicer expression, and its silencing exacerbates pressure-induced DNA damage. Moreover, pressure loading also activates ERK1/2 signaling molecules. Blockage of ERK1/2 signaling inhibits pressure-upregulated Dicer expression and exacerbates DNA damage by suppressing DNA damage response in hepatocytes. Our findings demonstrate that compressive stress loading induces hepatocyte DNA damage through the ERK1/2-Dicer signaling pathway, which provides evidence for a better understanding of the link between the altered mechanical environment and liver diseases.
肝组织力学微环境的改变被证明是导致肝细胞损伤甚至触发肝细胞癌发生的关键因素，但其中涉及的潜在机制尚不完全清楚。在这项研究中，我们使用定制的压力加载装置评估了压力加载对人肝细胞 DNA 损伤的影响。我们发现压力加载会导致 DNA 损伤和细胞周期 S 期停滞，并激活肝细胞中的 DNA 损伤反应。同时，压力加载上调了 Dicer 的表达，而其沉默会加剧压力诱导的 DNA 损伤。此外，压力加载还激活了 ERK1/2 信号分子。阻断 ERK1/2 信号会抑制压力上调的 Dicer 表达，并通过抑制肝细胞中的 DNA 损伤反应来加剧 DNA 损伤。我们的研究结果表明，压缩应激加载通过 ERK1/2-Dicer 信号通路诱导肝细胞 DNA 损伤，为更好地理解机械环境改变与肝脏疾病之间的联系提供了证据。
