Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
Cell Death Dis. 2023 Sep 5;14(9):590. doi: 10.1038/s41419-023-06092-5.
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.
肝内胆管癌（ICC）是一种原发性肝脏恶性肿瘤，其具有高度侵袭性和恶性的生物学行为。目前，有效的治疗策略有限。仑伐替尼对 ICC 的作用尚不清楚。在本研究中，我们发现 AZGP1 是仑伐替尼在 ICC 中的关键靶标，ICC 癌组织中 AZGP1 的低表达与患者预后不良相关。仑伐替尼是一种新型的 ICC 激动剂候选药物，通过调节 TGF-β1/Smad3 信号通路以 AZGP1 依赖性方式抑制 ICC-EMT。此外，我们发现仑伐替尼通过增加 AZGP1 基因启动子区域 H3K27Ac 的乙酰化水平来增加 AZGP1 的表达，从而抑制 ICC 细胞的 EMT。总之，仑伐替尼通过增加 AZGP1 基因启动子区域 H3K27Ac 的乙酰化水平来激活 AZGP1，并以 AZGP1 依赖性方式调节 TGF-β1/Smad3 信号通路，从而抑制 ICC-EMT。这项研究为仑伐替尼治疗 ICC 的机制提供了新的见解，并为新的治疗方法提供了理论依据。
