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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 11
Nov.  2022
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Article Contents

Research advances in traditional Chinese medicine in regulating epithelial-mesenchymal transformation to inhibit hepatocellular carcinoma metastasis

DOI: 10.3969/j.issn.1001-5256.2022.11.040
Research funding:

Natural Science Foundation of Shanghai (20ZR1458900);

Sailing Plan of Shanghai for Young Scientific and Technological Talents (20YF1450000)

More Information
  • Corresponding author: SONG Haiyan, songhy@126.com(ORCID: 0000-0003-2155-8110)
  • Received Date: 2022-03-28
  • Accepted Date: 2022-04-30
  • Published Date: 2022-11-20
  • Metastasis is an important factor for the high recurrence and mortality rates of hepatocellular carcinoma (HCC), and epithelial-mesenchymal transition (EMT) is an important mechanism of HCC metastasis. EMT is regulated by the transcription factors such as Snail, Twist, and ZEB which are mediated by a variety of signaling pathways including TGF-β, Wnt/β-catenin, and Notch. Inhibition of EMT-related molecules and signal pathways in HCC is considered as an important approach to inhibit the invasion and metastasis of HCC. Recent studies have shown that a variety of compound traditional Chinese medicine (TCM) formula or their effective constituents can inhibit the invasion and metastasis of HCC by arresting or reversing EMT in HCC. This article reviews the role and mechanism of EMT and recent studies on TCM drugs and their derived natural compounds in inhibiting the invasion and metastasis of HCC by regulating cell EMT, so as to provide a scientific basis for the TCM prevention and treatment of HCC metastasis and new ideas for HCC treatment.

     

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  • [1]
    SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
    [2]
    ZHAO P, JIANG DM, XIAN LF, et al. Mortality analysis of primary liver cancer in the mainland of China from 2004 to 2018[J]. Shanghai J Prev Med, 2021, 33: 881-886. DOI: 10.19428/j.cnki.sjpm.2021.21080.

    赵沛, 蒋栋铭, 鲜林峰, 等. 2004—2018年中国大陆地区原发性肝癌死亡率分析[J]. 上海预防医学, 2021, 33: 881-886. DOI: 10.19428/j.cnki.sjpm.2021.21080.
    [3]
    UCHINO K, TATEISHI R, SHⅡNA S, et al. Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors[J]. Cancer, 2011, 117(19): 4475-4483. DOI: 10.1002/cncr.25960.
    [4]
    PINZANI M. Epithelial-mesenchymal transition in chronic liver disease: fibrogenesis or escape from death?[J]. J Hepatol, 2011, 55(2): 459-465. DOI: 10.1016/j.jhep.2011.02.001.
    [5]
    MITTAL V. Epithelial mesenchymal transition in tumor metastasis[J]. Annu Rev Pathol, 2018, 13: 395-412. DOI: 10.1146/annurev-pathol-020117-043854.
    [6]
    LAMOUILLE S, XU J, DERYNCK R. Molecular mechanisms of epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2014, 15(3): 178-196. DOI: 10.1038/nrm3758.
    [7]
    CHEN J, CAO SW, CAI Z, et al. Epithelial-mesenchymal transition phenotypes of circulating tumor cells correlate with the clinical stages and cancer metastasis in hepatocellular carcinoma patients[J]. Cancer Biomark, 2017, 20(4): 487-498. DOI: 10.3233/CBM-170315.
    [8]
    HELLER M, PARIKH ND, FIDELMAN N, et al. Frontiers of therapy for hepatocellular carcinoma[J]. Abdom Radiol (NY), 2021, 46(8): 3648-3659. DOI: 10.1007/s00261-021-03065-0.
    [9]
    LIAO X, BU Y, JIA Q. Traditional Chinese medicine as supportive care for the management of liver cancer: Past, present, and future[J]. Genes Dis, 2020, 7(3): 370-379. DOI: 10.1016/j.gendis.2019.10.016.
    [10]
    LI XH, YUAN HX. Improving the efficacy of traditional Chinese medicine in treatment of primary liver cancer based on etiology and pathogenesis[J]. J Clin Hepatol, 2021, 37(9): 2001-2004. DOI: 10.3969/j.issn.1001-5256.2021.09.001.

    李秀惠, 袁慧鑫. 从病因病机入手提高中医药治疗原发性肝癌的疗效[J]. 临床肝胆病杂志, 2021, 37(9): 2001-2004. DOI: 10.3969/j.issn.1001-5256.2021.09.001.
    [11]
    BRABLETZ S, SCHUHWERK H, BRABLETZ T, et al. Dynamic EMT: a multi-tool for tumor progression[J]. EMBO J, 2021, 40(18): e108647. DOI: 10.15252/embj.2021108647.
    [12]
    KANG E, SEO J, YOON H, et al. The post-translational regulation of epithelial-mesenchymal transition-inducing transcription factors in cancer metastasis[J]. Int J Mol Sci, 2021, 22(7): 3591. DOI: 10.3390/ijms22073591.
    [13]
    LIU Z, WANG Y, DOU C, et al. Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma[J]. Theranostics, 2018, 8(17): 4649-4663. DOI: 10.7150/thno.26789.
    [14]
    DONG Y, ZHENG Q, WANG Z, et al. Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis[J]. J Hematol Oncol, 2019, 12(1): 112. DOI: 10.1186/s13045-019-0795-5.
    [15]
    GEORGAKOPOULOS-SOARES I, CHARTOUMPEKIS DV, KYRIAZOPOULOU V, et al. EMT factors and metabolic pathways in cancer[J]. Front Oncol, 2020, 10: 499. DOI: 10.3389/fonc.2020.00499.
    [16]
    HAO Y, BAKER D, TEN DIJKE P. TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis[J]. Int J Mol Sci, 2019, 20(11) : 2767. DOI: 10.3390/ijms20112767.
    [17]
    DERYNCK R, BUDI EH. Specificity, versatility, and control of TGF-β family signaling[J]. Sci Signal, 2019, 12(570): eaav5183. DOI: 10.1126/scisignal.aav5183.
    [18]
    GURZU S, KOBORI L, FODOR D, et al. Epithelial mesenchymal and endothelial mesenchymal transitions in hepatocellular carcinoma: a review[J]. Biomed Res Int, 2019, 2019: 2962580. DOI: 10.1155/2019/2962580.
    [19]
    DONGRE A, WEINBERG RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer[J]. Nat Rev Mol Cell Biol, 2019, 20(2): 69-84. DOI: 10.1038/s41580-018-0080-4.
    [20]
    HAN TS, HUR K, CHO HS, et al. Epigenetic associations between lncRNA/circRNA and miRNA in hepatocellular carcinoma[J]. Cancers (Basel), 2020, 12(9): 2622. DOI: 10.3390/cancers12092622.
    [21]
    TSUBAKIHARA Y, MOUSTAKAS A. Epithelial-mesenchymal transition and metastasis under the control of transforming growth factor β[J]. Int J Mol Sci, 2018, 19(11): 3672. DOI: 10.3390/ijms19113672.
    [22]
    PENG T. Clinical application of Biejiajian Pill in the treatment of liver cancer[J]. Chin J Integr Tradit West Med Liver Dis, 2020, 30(6): 481-483. DOI: 10.3969/j.issn.1005-0264.2020.06.001.

    彭涛. 鳖甲煎丸在肝癌治疗中的临床应用[J]. 中西医结合肝病杂志, 2020, 30(6): 481-483. DOI: 10.3969/j.issn.1005-0264.2020.06.001.
    [23]
    ZHONG XD, WEN B, SUN HT, et al. Mechanism of Biejiajian Wan against EMT of hepatocellular carcinoma cells through NF-κB signaling pathway[J]. Chin J Exp Med Formul, 2022, 28(1): 24-32. DOI: 10.13422/j.cnki.syfjx.20212421.

    钟晓丹, 文彬, 孙海涛, 等. 鳖甲煎丸通过NF-κB信号通路抑制肝癌细胞上皮间质转化的作用机制[J]. 中国实验方剂学杂志, 2022, 28(1): 24-32. DOI: 10.13422/j.cnki.syfjx.20212421.
    [24]
    ZHAO WT. Mechanism of Wnt/β-catenin signaling pathway regulating WB-F344 cell epithelial mesenchymal transition and intervention of Biejiajian pills[D]. Guangzhou: Southern Medical University, 2021.

    招文婷. Wnt/β-catenin信号通路调控WB-F344细胞上皮间质转化的分子机制及鳖甲煎丸的干预作用[D]. 广州: 南方医科大学, 2021.
    [25]
    ZHONG C, HUANG JH, CHEN QY, et al. Effects of Jianpi Huayu formula on Smad7 protein and epithelial mesenchymal transition of hepatocellular carcinoma cell[J]. China J Tradit Chin Med Pharm, 2017, 32(8): 3789-3792. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY201708124.htm

    钟崇, 黄俊海, 陈秋源, 等. 健脾化瘀法方药对肝癌细胞Smad7蛋白及上皮间质转化的影响[J]. 中华中医药杂志, 2017, 32(8): 3789-3792. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY201708124.htm
    [26]
    FENG KL, CHEN QL, XIE CF, et al. JianpiHuayu decoction inhibits migration, invasion and EMT of hepatomacarcinoma cell through regulation of exosome[J]. Tradit Chin Drug Res Clin Pharmacol, 2021, 32(12): 1745-1751. DOI: 10.19378/j.issn.1003-9783.2021.12.002.

    冯坤良, 陈清莲, 谢春凤, 等. 健脾化瘀方体外通过外泌体影响肝癌细胞的迁移、侵袭及上皮间质转化[J]. 中药新药与临床药理, 2021, 32(12): 1745-1751. DOI: 10.19378/j.issn.1003-9783.2021.12.002.
    [27]
    CHEN K, ZHANG YF. Clinical curative observation of using Jianpi Huayu decoction combined with chemotherapy in the treatment of 78cases of primary hepatocellular carcinoma (liver-depression and spleen-deficiency syndrome)[J]. J Sichuan Tradit Chin Med, 2017, 35(7): 108-110. https://www.cnki.com.cn/Article/CJFDTOTAL-SCZY201707046.htm

    陈科, 张月峰. 健脾化瘀方联合化疗治疗原发性肝癌(肝郁脾虚型)78例临床疗效观察[J]. 四川中医, 2017, 35(7): 108-110. https://www.cnki.com.cn/Article/CJFDTOTAL-SCZY201707046.htm
    [28]
    FANG Y, XIAO HJ, LI RT, et al. Effect of Fuzheng Kang'ai formula on anti-hepatoma by reversing EMT transformation of HepG2 cells[J]. Guid J Tradit Chin Med Pharm, 2019, 25(1): 60-63. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZB201901015.htm

    方瑜, 肖海娟, 李仁廷, 等. 扶正抗癌方通过逆转HepG2细胞EMT抗肝癌的实验研究[J]. 中医药导报, 2019, 25(1): 60-63. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZB201901015.htm
    [29]
    LIANG XJ, LIANG ST, JIANG WH, et al. Overview of the pharmacological effects of Ruanjian Hugan table and their experimental and clinical application in the treatment of liver diseases[J]. Intern Med China, 2020, 15(5): 568-570. DOI: 10.16121/j.cnki.cn45-1347/r.2020.05.17.

    梁雪婧, 梁水庭, 蒋汶洪, 等. 软坚护肝片的药理学作用及其在肝脏疾病治疗中的实验和临床应用研究概述[J]. 内科, 2020, 15(5): 568-570. DOI: 10.16121/j.cnki.cn45-1347/r.2020.05.17.
    [30]
    SUN Z, LI S, CHENG BB, et al. Research of mechanisms of Ruanjian Hugan table on inhibition of hepatocellular carcinoma migration and the epithelial mesenchymal cell transformation[J]. J Liaoning Univ Tradit Chin Med, 2020, 22(3): 22-25. DOI: 10.13194/j.issn.1673-842x.2020.03.007.

    孙振, 李书, 程彬彬, 等. 软坚护肝片含药血清对肝癌细胞迁移侵袭作用及机制[J]. 辽宁中医药大学学报, 2020, 22(3): 22-25. DOI: 10.13194/j.issn.1673-842x.2020.03.007.
    [31]
    ZHANG QB, MENG XT, JIA QA, et al. Herbal compound Songyou Yin and moderate swimming suppress growth and metastasis of liver cancer by enhancing immune function[J]. Integr Cancer Ther, 2016, 15(3): 368-375. DOI: 10.1177/1534735415622011.
    [32]
    ZHANG N, WANG LR, LI DD, et al. Interferon-α combined with herbal compound "Songyou Yin" effectively inhibits the increased invasiveness and metastasis by insufficient radiofrequency ablation of hepatocellular carcinoma in an animal model[J]. Integr Cancer Ther, 2018, 17(4): 1260-1269. DOI: 10.1177/1534735418801525.
    [33]
    ZHENG S, JIA Q, SHEN H, et al. Treatment with the herbal formula Songyou Yin inhibits epithelial-mesenchymal transition in hepatocellular carcinoma through downregulation of TGF-β1 expression and inhibition of the SMAD2/3 signaling pathway[J]. Oncol Lett, 2017, 13(4): 2309-2315. DOI: 10.3892/ol.2017.5700.
    [34]
    QIU JX, YANG JK. Use of "SRRS" recipe on treatment of late stage liver cancer patients and their experimental investigations[J]. Chin J Integr Tradit West Med, 1987, 7(5): 275-277. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZXJ198705008.htm

    邱佳信, 杨金坤. 健脾理气、清热解毒、软坚化痰方剂治疗晚期肝癌的临床观察及实验研究[J]. 中西医结合杂志, 1987, 7(5): 275-277. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZXJ198705008.htm
    [35]
    CHENG QB, YANG YP, WANG Y, et al. Effect of pseudobulbus cremastrae seu pleiones on apoptosis and epithelial-mesenchymal transition of hepatoma carcinoma cell[J]. Chin Med, 2021, 36(10): 2202-2207. DOI: 10.16368/j.issn.1674-8999.2021.10.459.

    程清波, 杨艳萍, 王滢, 等. 山慈菇对肝癌细胞凋亡和上皮间质转化的影响[J]. 中医学报, 2021, 36(10): 2202-2207. DOI: 10.16368/j.issn.1674-8999.2021.10.459.
    [36]
    YAN YQ, XIE J, WANG JF, et al. Scorpion inhibits epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma[J]. Exp Biol Med (Maywood), 2018, 243(7): 645-654. DOI: 10.1177/1535370218762514.
    [37]
    WANG KX, DU GH, QIN XM, et al. Compound Kushen Injection intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling[J]. Phytomedicine, 2021, 93: 153781. DOI: 10.1016/j.phymed.2021.153781.
    [38]
    FU J, LIU JL, LIU KJ, et al. Ginkgo biloba extract contains a mechanism by which medicated serum indirectly inhibits malignant progression of hepatocellular carcinoma cell lines[J]. J Ningxia Med Univ, 2021, 43(7): 665-770. DOI: 10.16050/j.cnki.issn1674-6309.2021.07.001.

    付江, 刘敬莉, 柳科军, 等. 银杏叶提取物含药血清间接抑制肝癌细胞株恶性进展的机制[J]. 宁夏医科大学学报, 2021, 43(7): 665-770. DOI: 10.16050/j.cnki.issn1674-6309.2021.07.001.
    [39]
    CAO W, ZHANG Y, LI A, et al. Curcumin reverses hepatic epithelial mesenchymal transition induced by trichloroethylene by inhibiting IL-6R/STAT3[J]. Toxicol Mech Methods, 2021, 31(8): 589-599. DOI: 10.1080/15376516.2021.1941463.
    [40]
    ZHAO Z, MALHOTRA A, SENG WY. Curcumin modulates hepatocellular carcinoma by reducing UNC119 expression[J]. J Environ Pathol Toxicol Oncol, 2019, 38(3): 195-203. DOI: 10.1615/JEnvironPatholToxicolOncol.2019029549.
    [41]
    DU H, GU J, PENG Q, et al. Berberine suppresses EMT in liver and gastric carcinoma cells through combination with TGFβR regulating TGF-β/Smad pathway[J]. Oxid Med Cell Longev, 2021, 2021: 2337818. DOI: 10.1155/2021/2337818.
    [42]
    ZHANG YB, ZHU J, XIAO JX, et al. Effects of ethanol extracts of hedyotis diffusa on proliferation of rat hepatocarcinoma cells by regulating DDR1[J]. J Xi'an Jiaotong Univ: Med Sci, 2016, 37(2): 279-282. DOI: 10.7652/jdyxb201602027.

    张彦兵, 朱娇, 肖菊香, 等. 白花蛇舌草总黄酮对TGF-β1诱导的肝癌MHCC97-H细胞EMT的逆转作用及其机制[J]. 西安交通大学学报(医学版), 2016, 37(2): 279-282. DOI: 10.7652/jdyxb201602027.
    [43]
    LYU MX, LIAO ZH, ZHOU H, et al. Saponin monomer I of Schizocapsa plantaginea Hance effect of epithelial mesenchymal transformation on the invasion and metastasis of human hepatocellular carcinoma SMMC-7721 by TGF-β1[J]. Chin Pharmacol Bull, 2020, 36(3): 408-413. DOI: 10.3969/j.issn.1001-1978.2020.03.021.

    吕美娴, 廖智红, 周欢, 等. 裂果薯皂苷单体Ⅰ通过TGF-β1调控上皮间质转化对人肝癌细胞SMMC-7721侵袭和转移的影响[J]. 中国药理学通报, 2020, 36(3): 408-413. DOI: 10.3969/j.issn.1001-1978.2020.03.021.
    [44]
    LIU M, XIONG CM, WANG ZY, et al. Effect of tanshinone ⅡA on phosphorylation of Smad3/Smad7 protein and epithelial mesenchymal transition of hepatocellular carcinoma cell line MHCC97H[J]. Guid J Tradit Chin Med Pharm, 2017, 23(10): 30-34. DOI: 10.13862/j.cnki.cn43-1446/r.2017.10.011.

    刘敏, 熊成名, 王子豫, 等. 丹参酮ⅡA对肝癌细胞MHCC97H Smad3/Smad7蛋白及上皮间质转化的影响[J]. 中医药导报, 2017, 23(10): 30-34. DOI: 10.13862/j.cnki.cn43-1446/r.2017.10.011.
    [45]
    QIN CD, MA DN, REN ZG, et al. Astragaloside IV inhibits metastasis in hepatoma cells through the suppression of epithelial-mesenchymal transition via the Akt/GSK-3β/β-catenin pathway[J]. Oncol Rep, 2017, 37(3): 1725-1735. DOI: 10.3892/or.2017.5389.
    [46]
    LIN ZK, LIU J, JIANG GQ, et al. Osthole inhibits the tumorigenesis of hepatocellular carcinoma cells[J]. Oncol Rep, 2017, 37(3): 1611-1618. DOI: 10.3892/or.2017.5403.
    [47]
    SONG FF, ZHANG YW, PAN ZF, et al. Resveratrol inhibits the migration, invasion and epithelialmesenchymal transition in liver cancer cells through upregulating miR-186-5p expression in vitro[J]. J Zhejiang Univ Med Sci, 2021, 50(5): 582-590. DOI: 10.3724/zdxbyxb-2021-0197.

    宋飞凤, 张轶雯, 潘宗富, 等. 白藜芦醇通过上调miR-186-5p表达抑制肝癌细胞迁移、侵袭和上皮-间质转化[J]. 浙江大学学报, 2021, 50(5): 582-590. DOI: 10.3724/zdxbyxb-2021-0197.
    [48]
    XING S, YU W, ZHANG X, et al. Isoviolanthin extracted from dendrobium officinale reverses TGF-β1-mediated epithelial-mesenchymal transition in hepatocellular carcinoma cells via deactivating the TGF-β/Smad and PI3K/Akt/mTOR signaling pathways[J]. Int J Mol Sci, 2018, 19(6): 1556. DOI: 10.3390/ijms19061556.
    [49]
    LIU P, ATKINSON SJ, AKBAREIAN SE, et al. Sulforaphane exerts anti-angiogenesis effects against hepatocellular carcinoma through inhibition of STAT3/HIF-1α/VEGF signalling[J]. Sci Rep, 2017, 7(1): 12651. DOI: 10.1038/s41598-017-12855-w.
    [50]
    CHO ES, KANG HE, KIM NH, et al. Therapeutic implications of cancer epithelial-mesenchymal transition (EMT)[J]. Arch Pharm Res, 2019, 42(1): 14-24. DOI: 10.1007/s12272-018-01108-7.
    [51]
    GAO YR, CHEN SJ, HOU YW, et al. Clinical effect of Huaier Granule sequential with radiofrequency ablation and TACE in treating primary hepatic carcinoma[J]. J Changchun Univ Chin Med, 2020, 36(4): 684-687. DOI: 10.13463/j.cnki.cczyy.2020.04.021.

    高远韧, 陈思佳, 侯英文, 等. TACE联合射频消融术序贯槐耳颗粒治疗原发性肝癌[J]. 长春中医药大学学报, 2020, 36(4): 684-687. DOI: 10.13463/j.cnki.cczyy.2020.04.021.
    [52]
    WANG H, SHAN L, WU XX, et al. Clinical efficacy of Qinggan Quai prescription combined with transcatheter arterial chemoembolization in treatment of advanced liver cancer with heat stasis[J]. Clin J Med Offic, 2021, 49(3): 306-308. DOI: 10.16680/j.1671-3826.2021.03.23.

    王昊, 单良, 吴孝雄, 等. 清肝祛癌方联合肝动脉化疗栓塞术治疗晚期热瘀型肝癌临床疗效[J]. 临床军医杂志, 2021, 49(3): 306-308. DOI: 10.16680/j.1671-3826.2021.03.23.
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