School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.
The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, China.
J Cell Mol Med. 2020 Jul;24(13):7405-7416. doi: 10.1111/jcmm.15356. Epub 2020 May 28.
As an outcome of chronic liver disease, liver fibrosis involves the activation of hepatic stellate cells (HSCs) caused by a variety of chronic liver injuries. It is important to explore approaches to inhibit the activation and proliferation of HSCs for the treatment of liver fibrosis. PLK1 is overexpressed in many human tumour cells and has become a popular drug target in tumour therapy. Therefore, further study of the function of PLK1 in the cell cycle is valid. In the present study, we found that PLK1 expression was elevated in primary HSCs isolated from CCl -induced liver fibrosis mice and LX-2 cells stimulated with TGF-β1. Knockdown of PLK1 inhibited α-SMA and Col1α1 expression and reduced the activation of HSCs in CCl -induced liver fibrosis mice and LX-2 cells stimulated with TGF-β1. We further showed that inhibiting the expression of PLK1 reduced the proliferation of HSCs and promoted HSCs apoptosis in vivo and in vitro. Furthermore, we found that the Wnt/β-catenin signalling pathway may be essential for PLK1-mediated HSCs activation. Together, blocking PLK1 effectively suppressed liver fibrosis by inhibiting HSC activation, which may provide a new treatment strategy for liver fibrosis.
作为慢性肝病的结果，肝纤维化涉及由各种慢性肝损伤引起的肝星状细胞（HSCs）的激活。探索抑制 HSCs 的激活和增殖以治疗肝纤维化的方法非常重要。PLK1 在许多人类肿瘤细胞中过度表达，已成为肿瘤治疗中一种热门的药物靶点。因此，进一步研究 PLK1 在细胞周期中的功能是有效的。在本研究中，我们发现 PLK1 在 CCl4 诱导的肝纤维化小鼠原代 HSCs 和 TGF-β1 刺激的 LX-2 细胞中表达上调。PLK1 敲低抑制了α-SMA 和 Col1α1 的表达，并减少了 CCl4 诱导的肝纤维化小鼠和 TGF-β1 刺激的 LX-2 细胞中 HSCs 的激活。我们进一步表明，抑制 PLK1 的表达减少了 HSCs 的增殖，并促进了体内和体外 HSCs 的凋亡。此外，我们发现 Wnt/β-catenin 信号通路可能是 PLK1 介导的 HSCs 激活所必需的。总之，阻断 PLK1 通过抑制 HSC 激活有效地抑制了肝纤维化，这可能为肝纤维化提供一种新的治疗策略。
