Matrine improves the hepatic microenvironment and reverses epithelial-mesenchymal transition in hepatocellular carcinoma by inhibiting the Wnt-1/β-catenin signaling pathway

Jianfei Shi; Hua Zhang; Guangjie Han; Jinfeng Wang; Xin Han; Man Zhao; Xiaoling Duan; Lili Mi; Ning Li; Xiaolei Yin; Cuizhen Li; Fei Yin

Matrine improves the hepatic microenvironment and reverses epithelial-mesenchymal transition in hepatocellular carcinoma by inhibiting the Wnt-1/β-catenin signaling pathway

Am J Transl Res. 2023 Aug 15;15(8):5047-5070. eCollection 2023.

Authors

Jianfei Shi¹, Hua Zhang², Guangjie Han¹, Jinfeng Wang¹, Xin Han¹, Man Zhao¹, Xiaoling Duan¹, Lili Mi¹, Ning Li¹, Xiaolei Yin¹, Cuizhen Li¹, Fei Yin¹

Affiliations

¹ Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University Shijiazhuang 050019, Hebei, P. R. China.
² Department of Infectious Diseases, The Fourth Hospital of Hebei Medical University Shijiazhuang 050019, Hebei, P. R. China.

PMID: 37692966
PMCID: PMC10492086

Abstract

Objective: Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality. Despite rapid progress in targeted therapy and immunotherapy for HCC over the past 10 years, the overall efficacy remains unsatisfactory. This is mainly due to the presence of an intrahepatic microenvironment of cirrhosis in HCC patients, leading to cancer recurrence and drug resistance.

Methods: In this study, we investigated the correlations between the Wnt-1/β-catenin signaling pathway and the prognosis as well as liver function of HCC patients. Additionally, we conducted in vitro experiments using different concentrations of matrine on HuH-7 cells. Furthermore, we verified the associations between the Wnt-1/β-catenin signaling pathway, inflammation, and epithelial-mesenchymal transition (EMT) in a rat model of pre-hepatocellular carcinoma. Finally, matrine was employed to treat pre-hepatocellular carcinoma in rats and patients with advanced hepatocellular carcinoma.

Results: The results demonstrated the activation of the Wnt-1/β-catenin signaling pathway, the occurrence of EMT, and exacerbated inflammation in human HCC tissues. In HuH-7 cell experiments, matrine effectively downregulated the Wnt-1/β-catenin pathway, reversed EMT, and suppressed migration and invasion of HCC cells. In the rat model of pre-hepatocellular carcinoma, matrine dose-dependently inhibited the activation of the Wnt-1/β-catenin signaling pathway, reversed the occurrence of EMT, and alleviated liver inflammation. Matrine analogues exhibited promising hepatoprotective effects in patients with advanced HCC.

Conclusions: Matrine can reverse EMT, alleviate intrahepatic inflammation, and counteract immune depletion by inhibiting the Wnt-1/β-catenin signaling pathway in HCC.

Keywords: Matrine; Solt-Farber rat model; Wnt-1/β-catenin signaling pathway; cirrhosis; epithelial-mesenchymal transition (EMT); hepatocellular carcinoma (HCC).