Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer  

作　　者：Zhen Huang Fan-Ying Meng Lin-Zhu Lu Qian-Qian Guo Chang-Jun Lv Nian-Hua Tan Zhe Deng Jun-Yi Chen Zi-Shu Zhang Bo Zou Hong-Ping Long Qing Zhou Sha Tian Si Mei Xue-Fei Tian 

机构地区：[1]College of Integrated Chinese and Western Medicine,Hunan University of Chinese Medicine,Changsha 410208,Hunan Province,China [2]Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine,Hunan University of Chinese Medicine,Changsha 410208,Hunan Province,China [3]Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment,Hunan University of Chinese Medicine,Changsha 410208,Hunan Province,China [4]The First Clinical College of Traditional Chinese Medicine,Hunan University of Traditional Chinese Medicine,Changsha 410007,Hunan Province,China [5]Department of Hepatology,Hunan University of Chinese Medicine,Changsha 410007,Hunan Province,China [6]The First Hospital of Hunan University of Chinese Medicine,Hunan University of Chinese Medicine,Changsha 410007,Hunan Province,China [7]Faculty of Medicine,Hunan University of Chinese Medicine,Changsha 410208,Hunan Province,China

出　　处：《World Journal of Gastroenterology》2024年第29期3511-3533,共23页世界胃肠病学杂志（英文版）

基　　金：Supported by National Natural Science Foundation of China,No.82074450;Education Department of Hunan Province,No.21A0243,No.21B0374,No.22B0397,and No.22B0392;Research Project of"Academician Liu Liang Workstation"of Hunan University of Traditional Chinese Medicine,No.21YS003;Hunan Administration of Traditional Chinese Medicine,No.B2023001 and No.B2023009;Hunan Provincial Natural Science Foundation of China,No.2023JJ40481。

摘　　要：BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

关 键 词：Calculus bovis M2 tumor-associated macrophage polarization Liver cancer Wnt/β-catenin pathway Tumor microenvironment 

分 类 号：R73[医药卫生—肿瘤] R28[医药卫生—临床医学]