2. Academic Validation
  3. Fangchinoline inhibits metastasis and reduces inflammation-induced epithelial-mesenchymal transition by targeting the FOXM1-ADAM17 axis in hepatocellular carcinoma

Fangchinoline inhibits metastasis and reduces inflammation-induced epithelial-mesenchymal transition by targeting the FOXM1-ADAM17 axis in hepatocellular carcinoma

  • Cell Signal. 2024 Dec:124:111467. doi: 10.1016/j.cellsig.2024.111467.
Liyun Zheng 1,  Vinothkumar Rajamanickam 2,  Mengyuan Wang 3,  Huajun Zhang 2,  Shiji Fang 1,  Michael Linnebacher 4,  A M Abd El-Aty 5,  Xinbin Zhang 6,  Yeyu Zhang 2,  Jianbo Wang 2,  Minjiang Chen 7,  Zhongwei Zhao 8,  Jiansong Ji 9
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
  • 2 Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
  • 3 Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China.
  • 4 Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, Rostock 18059, Germany.
  • 5 Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt.
  • 6 Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
  • 7 Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China. Electronic address: minjiangchenv@163.com.
  • 8 Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China. Electronic address: Zhaozw79@163.com.
  • 9 Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China. Electronic address: jijiansong@zju.edu.cn.
PMID: 39393566 DOI: 10.1016/j.cellsig.2024.111467
Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Efforts have been focused on developing new anti-HCC agents and understanding their pharmacology. However, few agents have been able to effectively combat tumor growth and invasiveness due to the rapid progression of HCC. In this study, we discovered that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moore, effectively inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. FAN treatment also led to the suppression of IL6 and IL1β release, as well as the expression of inflammation-related proteins such as COX-2 and iNOS, and the activation of the NF-κB pathway, thereby reducing inflammation-related EMT. Additionally, FAN directly bound to forkhead box protein M1 (FOXM1), resulting in decreased levels of FOXM1 proteins and disruption of the FOXM1-ADAM17 axis. Our in vivo findings confirmed that FAN effectively hindered the growth and lung metastasis of HCCLM3-xenograft tumors. Importantly, the upregulation of FOXM1 in HCC tissue suggested that targeting FOXM1 inhibition with FAN or its inhibitors could be a promising therapeutic approach for HCC. Overall, this study elucidated the anti-tumor effects and potential pharmacological mechanisms of FAN, and proposed that targeting FOXM1 inhibition may be an effective therapeutic strategy for HCC with potential clinical applications.

Keywords

ADAM17; Anti-tumor; FOXM1; Fangchinoline; Hepatocellular carcinoma.

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