AZGP1（α2-糖蛋白酶抑制蛋白1）通过TGF-β1/Smad3信号通路激活, 抑制亮矾替尼对肝内胆管癌上皮间质转化的影响.
AZGP1 activation by lenvatinib suppresses intrahepatic cholangiocarcinoma epithelial-mesenchymal transition through the TGF-β1/Smad3 pathway.
发表日期：2023 Sep 05
作者：
Liming Deng, Wenming Bao, Baofu Zhang, Sina Zhang, Ziyan Chen, Xuewen Zhu, Bangjie He, Lijun Wu, Xiaohu Chen, Tuo Deng, Bo Chen, Zhengping Yu, Yi Wang, Gang Chen
来源：
Cell Death & Disease
摘要：
肝内胆管癌（ICC）是一种原发性肝恶性肿瘤，具有高度侵袭和恶性生物行为特征。目前有效的治疗策略有限。Lenvatinib对ICC的作用尚不清楚。在本研究中，我们发现AZGP1是Lenvatinib在ICC中的关键靶点，其在ICC癌组织中的低表达与患者预后不良相关。Lenvatinib是一种新型的ICC AZGP1激动剂候选药物，通过以AZGP1为依赖因子，调节TGF-β1/Smad3信号通路，抑制ICC-EMT。此外，我们发现Lenvatinib能够通过增加AZGP1基因启动子区域H3K27Ac乙酰化水平，提高AZGP1表达，从而抑制ICC细胞的EMT。总之，Lenvatinib通过增加AZGP1基因启动子区域H3K27Ac乙酰化水平激活AZGP1，并以AZGP1为依赖因子调节TGF-β1/Smad3信号通路，抑制ICC-EMT。本研究揭示了Lenvatinib治疗ICC的机制，并为新的治疗方法提供了理论基础。© 2023. The Author(s).
Intrahepatic cholangiocarcinoma (ICC) is a primary liver malignancy and is characterized by highly aggressive and malignant biological behavior. Currently, effective treatment strategies are limited. The effect of lenvatinib on ICC is unknown. In this study, we found that AZGP1 was the key target of lenvatinib in ICC, and its low expression in ICC cancer tissues was associated with a poor prognosis in patients. Lenvatinib is a novel AZGP1 agonist candidate for ICC that inhibits ICC-EMT by regulating the TGF-β1/Smad3 signaling pathway in an AZGP1-dependent manner. Furthermore, we found that lenvatinib could increase AZGP1 expression by increasing the acetylation level of H3K27Ac in the promoter region of the AZGP1 gene, thereby inhibiting EMT in ICC cells. In conclusion, lenvatinib activates AZGP1 by increasing the acetylation level of H3K27Ac on the AZGP1 promoter region and regulates the TGF-β1/Smad3 signaling pathway in an AZGP1-dependent manner to inhibit ICC-EMT. This study offers new insight into the mechanism of lenvatinib in the treatment of ICC and provides a theoretical basis for new treatment methods.© 2023. The Author(s).