Jiedu Recipe, a compound Chinese herbal medicine, inhibits cancer stemness in hepatocellular carcinoma via Wnt/β-catenin pathway under hypoxia

IF 4.2 2区医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Journal of Integrative Medicine-Jim Pub Date : 2023-09-01 DOI:10.1016/j.joim.2023.06.008

Bing-jie Guo , Yi Ruan , Ya-jing Wang , Chu-lan Xiao , Zhi-peng Zhong , Bin-bin Cheng , Juan Du , Bai Li , Wei Gu , Zi-fei Yin

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引用次数: 2

Abstract

Objective

Jiedu Recipe (JR), a Chinese herbal remedy, has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma (HCC). This work investigated the mechanism of JR in HCC treatment.

Methods

The chemical constituents of JR were detected using liquid chromatography-mass spectrometry. The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid (mRNA) microarray chip assay, followed by experimental validation in human HCC cells (SMMC-7721 and Huh7) in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo. HCC cell characteristics of proliferation, migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide, wound healing and Transwell assays, respectively. Image-iT™ Hypoxia Reagent was added to reveal hypoxic conditions. Stem cell sphere formation assay was used to detect the stemness. Epithelial-mesenchymal transition (EMT) markers like E-cadherin, vimentin and α-smooth muscle actin, and pluripotent transcription factors including nanog homeobox, octamer-binding transcription factor 4, and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction. Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin pathway.

Results

According to network pharmacology and mRNA microarray chip analysis, JR may potentially act on hypoxia and inhibit the Wnt/β-catenin pathway. In vitro and in vivo experiments showed that JR significantly decreased hypoxia, and suppressed HCC cell features of proliferation, migration and invasion; furthermore, the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR. Results based on the co-administration of JR and an agonist (LiCl) or inhibitor (IWR-1-endo) verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/β-catenin pathway.

Conclusion

JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/β-catenin pathway under hypoxic conditions.

Please cite this article as: Guo BJ, Ruan Y, Wang YJ, Xiao CL, Zhong ZP, Cheng BB, Du J, Li B, Gu W, Yin ZF. Jiedu Recipe, a compound Chinese herbal medicine, inhibits cancer stemness in hepatocellular carcinoma via Wnt/β-catenin pathway under hypoxia. J Integr Med. 2023; 21(5): 474–486.

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解毒方是一种复方中草药，在低氧条件下通过Wnt/β-catenin途径抑制肝细胞癌癌症干。

目的：中药解毒方能延长肝细胞癌（HCC）患者的总生存时间，降低复发率和转移率。本工作探讨了JR在HCC治疗中的作用机制。方法：采用液相色谱-质谱联用技术对JR的化学成分进行检测。使用网络药理学和信使核糖核酸（mRNA）微阵列芯片分析筛选JR的潜在抗HCC机制，然后在体外人HCC细胞（SMMC-7721和Huh7）和体内HCC裸鼠皮下移植模型中进行实验验证。分别用噻唑蓝-溴化四氮唑、伤口愈合和Transwell试验研究了缺氧环境下HCC细胞的增殖、迁移和侵袭特性。图像iT™ 添加缺氧试剂以揭示缺氧条件。干细胞球形成试验用于检测干度。使用蛋白质印迹和实时聚合酶链反应分析上皮-间充质转化（EMT）标记物，如E-钙粘蛋白、波形蛋白和α-平滑肌肌动蛋白，以及多能干转录因子，包括nanog同源盒、八聚体结合转录因子4和性别决定区Y盒蛋白2。Western印迹法检测JR在低氧条件下的抗HCC作用，涉及Wnt/β-catenin通路。结果：根据网络药理学和mRNA微阵列芯片分析，JR可能对缺氧有潜在作用，并抑制Wnt/β-catenin通路。体外和体内实验表明，JR能显著降低缺氧，抑制HCC细胞的增殖、迁移和侵袭；此外，JR抑制了低氧诱导的HCC细胞中EMT和干性标志物表达的增加。基于JR和激动剂（LiCl）或抑制剂（IWR-1-endo）共同给药的结果证实，JR通过阻断Wnt/β-catenin途径抑制了缺氧下HCC癌症的干样特性。结论：JR在低氧条件下通过阻断Wnt/β-catenin通路抑制癌症干细胞，发挥抗肝癌的作用。请引用本文为：郭BJ，阮Y，王YJ，肖CL，钟ZP，程BB，杜J，李B，顾W，尹ZF。解毒方是一种复方中草药，在低氧条件下通过Wnt/β-catenin途径抑制肝细胞癌癌症干。国际医学杂志，2023；21（5）：474-486。

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来源期刊

Journal of Integrative Medicine-Jim Medicine-Complementary and Alternative Medicine

CiteScore

9.20

自引率

4.20%

发文量

3319

期刊介绍： The predecessor of JIM is the Journal of Chinese Integrative Medicine (Zhong Xi Yi Jie He Xue Bao). With this new, English-language publication, we are committed to make JIM an international platform for publishing high-quality papers on complementary and alternative medicine (CAM) and an open forum in which the different professions and international scholarly communities can exchange views, share research and their clinical experience, discuss CAM education, and confer about issues and problems in our various disciplines and in CAM as a whole in order to promote integrative medicine. JIM is indexed/abstracted in: MEDLINE/PubMed, ScienceDirect, Emerging Sources Citation Index (ESCI), Scopus, Embase, Chemical Abstracts (CA), CAB Abstracts, EBSCO, WPRIM, JST China, Chinese Science Citation Database (CSCD), and China National Knowledge Infrastructure (CNKI). JIM Editorial Office uses ThomsonReuters ScholarOne Manuscripts as submitting and review system (submission link: http://mc03.manuscriptcentral.com/jcim-en). JIM is published bimonthly. Manuscripts submitted to JIM should be written in English. Article types include but are not limited to randomized controlled and pragmatic trials, translational and patient-centered effectiveness outcome studies, case series and reports, clinical trial protocols, preclinical and basic science studies, systematic reviews and meta-analyses, papers on methodology and CAM history or education, conference proceedings, editorials, commentaries, short communications, book reviews, and letters to the editor. Our purpose is to publish a prestigious international journal for studies in integrative medicine. To achieve this aim, we seek to publish high-quality papers on any aspects of integrative medicine, such as acupuncture and traditional Chinese medicine, Ayurveda medicine, herbal medicine, homeopathy, nutrition, chiropractic, mind-body medicine, taichi, qigong, meditation, and any other modalities of CAM; our commitment to international scope ensures that research and progress from all regions of the world are widely covered. These ensure that articles published in JIM have the maximum exposure to the international scholarly community. JIM can help its authors let their papers reach the widest possible range of readers, and let all those who share an interest in their research field be concerned with their study.