School of Basic Medical Science, Chengdu Medical College, Chengdu, 610500, China; Sichuan Clinical Research Center for Geriatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.
School of Basic Medical Science, Chengdu Medical College, Chengdu, 610500, China.
Biochem Biophys Res Commun. 2020 May 28;526(2):314-320. doi: 10.1016/j.bbrc.2020.03.086. Epub 2020 Mar 21.
Aberrant activation of Hedgehog signaling is considered as the key player in hepatic stellate cell (HSC) activation involved in liver fibrosis (LF). The glioma-associated protein gene (GLI) has a predicted paired box 6 (PAX6)-binding site within its transcribed region. Therefore, this study aimed to investigate the relationship between PAX6 and GLI and their contribution to HSC activation and proliferation. PAX6 expression was upregulated in platelet-derived growth factor-BB (PDGF-BB)-induced LX-2 cells. The activation and proliferation of HSC were inhibited by interference of PAX6 with short hairpin RNA (shPAX6) via curbing Hedgehog signaling. Notably, PAX6 directly bound to the promoter sequence of GLI1 independent of the PTCH/SMO axis. Therefore, we propose that PAX6 upregulation induces HSC activation and proliferation through crosstalk with GLI1 signaling. Thus, these novel mechanistic insights involving the PAX6-mediated regulation of the activation and proliferation of HSC may provide a new therapeutic target for LF.
Hedgehog 信号通路的异常激活被认为是肝星状细胞 (HSC) 激活的关键因素，而后者与肝纤维化 (LF) 有关。神经胶质瘤相关蛋白基因 (GLI) 在其转录区域内具有预测的配对盒 6 (PAX6) 结合位点。因此，本研究旨在探讨 PAX6 和 GLI 之间的关系及其对 HSC 激活和增殖的贡献。血小板衍生生长因子-BB (PDGF-BB) 诱导的 LX-2 细胞中 PAX6 表达上调。通过短发夹 RNA (shPAX6) 干扰 PAX6 抑制 Hedgehog 信号通路，可抑制 HSC 的激活和增殖。值得注意的是，PAX6 可独立于 PTCH/SMO 轴直接与 GLI1 启动子序列结合。因此，我们提出 PAX6 上调通过与 GLI1 信号通路的串扰诱导 HSC 激活和增殖。因此，这些涉及 PAX6 介导的 HSC 激活和增殖的新机制见解可能为 LF 提供新的治疗靶点。
