Yan Qi, Pan Linxin, Qi Shunli, Liu Fang, Wang Zhen, Qian Cheng, Chen Lijian, Du Jian
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
The School of Life Science, Anhui Medical University, Hefei, China.
Front Cell Dev Biol. 2021 Mar 18;9:634902. doi: 10.3389/fcell.2021.634902. eCollection 2021.
The therapeutic approach of liver fibrosis is still an unsolved clinical problem worldwide. Notably, the accumulation of extracellular matrix (ECM) in the liver is mediated by the production of cytokines and growth factors, such as transforming growth factor-β1 (TGF-β1) in hepatic stellate cells (HSCs). Ring finger protein 2 (RNF2) was identified as the catalytic subunit of polycomb repressive complex 1 (PRC1), mediating the monoubiquitination of histone H2A. In recent years, a growing amount of evidence suggests that RNF2 may play an important role in multiple pathological processes involved in cancer. Here, we explored the role of RNF2 in liver fibrogenesis and its potential mechanisms. The results showed that RNF2 was up-regulated in human fibrotic liver tissue. Knockdown of RNF2 led to a decreasing expression of collagen1 and α-smooth muscle actin (α-SMA) in LX-2 cells, which was upregulated by RNF2 overexpression. Moreover, RNF2 overexpression significantly promoted TGF-β1-induced LX-2 cell proliferation but decreased apoptosis. Furthermore, knockdown of RNF2 inhibited the activation of ERK/p38 signaling pathways induced by TGF-β1. These data suggested that RNF2 is an effective pro-fibrogenic factor for HSC activation via ERK/p38 signaling pathway. RNF2 inhibition might be a promising therapeutic target for liver fibrosis.
肝纤维化的治疗方法在全球范围内仍是一个尚未解决的临床问题。值得注意的是，肝脏中细胞外基质（ECM）的积累是由细胞因子和生长因子的产生介导的，例如肝星状细胞（HSCs）中的转化生长因子-β1（TGF-β1）。环指蛋白2（RNF2）被鉴定为多梳抑制复合物1（PRC1）的催化亚基，介导组蛋白H2A的单泛素化。近年来，越来越多的证据表明RNF2可能在癌症相关的多种病理过程中发挥重要作用。在此，我们探讨了RNF2在肝纤维化形成中的作用及其潜在机制。结果显示，RNF2在人肝纤维化组织中上调。敲低RNF2导致LX-2细胞中胶原蛋白1和α-平滑肌肌动蛋白（α-SMA）的表达降低，而RNF2过表达则使其上调。此外，RNF2过表达显著促进TGF-β1诱导的LX-2细胞增殖，但减少细胞凋亡。此外，敲低RNF2抑制了TGF-β1诱导的ERK/p38信号通路的激活。这些数据表明，RNF2是通过ERK/p38信号通路激活肝星状细胞的一种有效的促纤维化因子。抑制RNF2可能是肝纤维化一个有前景的治疗靶点。
