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

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

doi:10.1016/j.joim.2024.10.002

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

J Integr Med. 2024 Oct 18:S2095-4964(24)00395-9. doi: 10.1016/j.joim.2024.10.002. Online ahead of print.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Pharmacy, Tianjin Rehabilitation and Recuperation Center, Joint Logistics Support Force, Tianjin 300000, China.
⁴ Department of Pulmonary and Critical Care Medicine, Tongji Hospital School of Medicine, Tongji University, Shanghai 200065, China.
⁵ Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
⁶ Department of General Practice, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
⁷ 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. Electronic address: changquanling@smmu.edu.cn.
⁸ 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. Electronic address: cbb8202@smmu.edu.cn.

PMID: 39521704
DOI: 10.1016/j.joim.2024.10.002

Abstract

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 through EGFR-TFEB signaling. Our study provides a potential strategy for retarding tumor metastasis by targeting H-TDE secretion. Please cite this article as: Jia WT, Xiang S, Zhang JB, Yuan JY, Wang YQ, Liang SF, Lin WF, Zhai XF, Shang Y, Ling CQ, Cheng BB. Jiedu recipe, a compound Chinese herbal medicine, suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment through the EGFR-TFEB signaling pathway. J Integr Med. 2024; Epub ahead of print.

Keywords: Hypoxia; Jiedu recipe; Premetastatic niches; Quercetin; Secretory autophagy; Tumor-derived exosomes.