Jiedu recipe,a compound Chinese herbal medicine,suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment  

作　　者：Wen-tao Jia Shuang Xiang Jin-bo Zhang Jia-ying Yuan Yu-qian Wang Shu-fang Liang Wan-fu Lin Xiao-feng Zhai Yan Shang Chang-quan Ling Bin-bin Cheng 

机构地区：[1]Oncology Department of Traditional Chinese Medicine,the First Affiliated Hospital of Naval Medical University,Shanghai 200433,China [2]Faculty of Traditional Chinese Medicine,Naval Medical University,Shanghai 200043,China [3]Department of General Practice,the First Affiliated Hospital of Naval Medical University,Shanghai 200433,China [4]Department of Pharmacy,Tianjin Rehabilitation and Recuperation Center,Joint Logistics Support Force,Tianjin 300000,China [5]Department of Pulmonary and Critical Care Medicine,Tongji Hospital School of Medicine,Tongji University,Shanghai 200065,China

出　　处：《Journal of Integrative Medicine》2024年第6期696-708,共13页结合医学学报（英文版）

基　　金：supported by the grants from National Natural Science Foundation of China(No.82030117,82074203,82170033,and 82374540);Special Fund for Research on Community Medicine and Health Management in Shanghai(No.2023SQ01);Medical Research Project of Health Commission of Shanghai Hongkou District(No.HW2302-43);Special Medical Basic Research Project of the First Affiliated Hospital of Naval Medical University(No.2021JCMS12);Wild Goose Array Project of Zhengzhou Center of Chinese People’s Liberation Army Joint Logistic Support Force。

摘　　要：Objective:Tumor-derived exosomes(TDEs)play crucial roles in intercellular communication.Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis.Jiedu recipe(JR),a traditional Chinese medicinal formula,has demonstrated efficacy in preventing the metastasis of hepatocellular carcinoma(HCC).However,the underlying mechanism remains largely unknown.Methods:Animal experiments were performed to investigate the metastasis-preventing effects of JR.Bioinformatics analysis and in vitro assays were conducted to explore the potential targets and active components of JR.TDEs were assessed using nanoparticle tracking analysis(NTA)and Western blotting(WB).Exosomes derived from normoxic or hypoxic HCC cells(H-TDEs)were collected to establish premetastatic mouse models.JR was intragastrically administered to evaluate its metastasis-preventive effects.WB and lysosomal staining were performed to investigate the effects of JR on lysosomal function and autophagy.Bioinformatics analysis,WB,NTA,and immunofluorescence staining were used to identify the active components and potential targets of JR.Results:JR effectively inhibited subcutaneous-tumor-promoted lung premetastatic niche development and tumor metastasis.It inhibited the release of exosomes from tumor cells under hypoxic condition.JR treatment promoted both lysosomal acidification and suppressed secretory autophagy,which were dysregulated in hypoxic tumor cells.Quercetin was identified as the active component in JR,and the epidermal growth factor receptor(EGFR)was identified as a potential target.Quercetin inhibited EGFR phosphorylation and promoted the nuclear translocation of transcription factor EB(TFEB).Hypoxia-impaired lysosomal function was restored,and secretory autophagy was alleviated by quercetin treatment.Conclusion:JR suppressed HCC metastasis by inhibiting hypoxia-stimulated exosome release,restoring lysosomal function,and suppressing secretory autophagy.Quercetin acted as a key component of JR and regulated TDE release thr

关 键 词：Hypoxia Jiedu recipe Tumor-derived exosomes Premetastatic niches Secretory autophagy Quercetin 

分 类 号：R285.5[医药卫生—中药学]