Bufalin targeting CAMKK2 inhibits the occurrence and development of intrahepatic cholangiocarcinoma through Wnt/β-catenin signal pathway

作者：Huhu Zhang, Xiaolei Dong, Xiaoyan Ding, Guoxiang Liu, Fanghao Yang, Qinghang Song, Hongxiao Sun, Guang Chen, Shuang Li, Ya Li, Mengjun Wang, Tingting Guo, Zhe Zhang, Bing Li, Lina Yang · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04613-6 · 被引用次数：29 · 研究领域：Wnt/β-catenin signaling in development and cancer、Developmental Biology and Gene Regulation、Protease and Inhibitor Mechanisms

Abstract Background Intrahepatic cholangiocarcinoma (ICC) accounts for about 15% of primary liver cancer, and the incidence rate has been rising in recent years. Surgical resection is the best treatment for ICC, but the 5-year survival rate is less than 30%. ICC signature genes are crucial for the early diagnosis of ICC, so it is especially important to find its signature genes and therapeutic drug. Here, we studied that bufalin targeting CAMKK2 promotes mitochondrial dysfunction and inhibits the occurrence and metastasis of intrahepatic cholangiocarcinoma through Wnt/β-catenin signal pathway. Methods IC50 of bufalin in ICC cells was determined by CCK8 and invasive and migratory abilities were verified by wound healing, cell cloning, transwell and Western blot. IF and IHC verified the expression of CAMKK2 between ICC patients and normal subjects. BLI and pull-down demonstrated the binding ability of bufalin and CAMKK2. Bioinformatics predicted whether CAMKK2 was related to the Wnt/β-catenin pathway. SKL2001, an activator of β-catenin, verified whether bufalin acted through this pathway. In vitro and in vivo experiments verified whether overexpression of CAMKK2 affects the proliferative and migratory effects of ICC. Transmission electron microscopy verified mitochondrial integrity. Associated Ca 2+ levels verified the biological effects of ANXA2 on ICC. Results It was found that bufalin inhibited the proliferation and migration of ICC, and CAMKK2 was highly expressed in ICC, a...