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

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

外文摘要：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 preme-tastatic 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 epi-dermal growth factor receptor(EGFR)was identified as a potential target.Quercetin inhibited EGFR phos-phorylation 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 through EGFR-TFEB signaling.Our study provides a potential strategy for retarding tumor metastasis by targeting H-TDE secretion.

外文关键词：

HypoxiaJiedu recipeTumor-derived exosomesPremetastatic nichesSecretory autophagyQuercetin

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

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作者单位：

Oncology Department of Traditional Chinese Medicine,the First Affiliated Hospital of Naval Medical University,Shanghai 200433,China

Faculty of Traditional Chinese Medicine,Naval Medical University,Shanghai 200043,China

Department of General Practice,the First Affiliated Hospital of Naval Medical University,Shanghai 200433,China

Department of Pharmacy,Tianjin Rehabilitation and Recuperation Center,Joint Logistics Support Force,Tianjin 300000,China

Department of Pulmonary and Critical Care Medicine,Tongji Hospital School of Medicine,Tongji University,Shanghai 200065,China

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关键词：

Hypoxia Jiedu recipe Tumor-derived exosomes Premetastatic niches Secretory autophagy Quercetin

出版年：

2024

DOI：

10.1016/j.joim.2024.10.002

结合医学学报(英文版)

上海市中西医结合学会,上海长海医院

结合医学学报(英文版)

CSTPCD

影响因子：0.711

ISSN：2095-4964

年,卷(期)：2024.22(6)