AZGP1 activation by lenvatinib suppresses intrahepatic cholangiocarcinoma epithelial-mesenchymal transition through the TGF-β1/Smad3 pathway

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

doi:10.1038/s41419-023-06092-5

AZGP1 activation by lenvatinib suppresses intrahepatic cholangiocarcinoma epithelial-mesenchymal transition through the TGF-β1/Smad3 pathway

Cell Death Dis. 2023 Sep 5;14(9):590. doi: 10.1038/s41419-023-06092-5.

Authors

Liming Deng^#^{1

2

3}, Wenming Bao^#^{1

2}, Baofu Zhang^#^{1

2}, Sina Zhang^{1

2}, Ziyan Chen^{1

2}, Xuewen Zhu^{1

2}, Bangjie He^{1

2}, Lijun Wu^{1

2}, Xiaohu Chen⁴, Tuo Deng^{1

2}, Bo Chen^{1

2}, Zhengping Yu^{1

2}, Yi Wang⁵, Gang Chen^{6

7

8}

Affiliations

¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
² 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.
³ The Second Affiliated Hospital, Department of General Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
⁴ Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
⁵ Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China. wang.yi@wmu.edu.cn.
⁶ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. chen.gang@wmu.edu.cn.
⁷ 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. chen.gang@wmu.edu.cn.
⁸ Hepatobiliary Pancreatic Tumor Bioengineering Cross International Joint Laboratory of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. chen.gang@wmu.edu.cn.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipokines
Bile Duct Neoplasms*
Bile Ducts, Intrahepatic
Cholangiocarcinoma*
Epithelial-Mesenchymal Transition
Humans
Transforming Growth Factor beta1

Substances

lenvatinib
Transforming Growth Factor beta1
AZGP1 protein, human
Adipokines