中医药调控Hedgehog信号通路防治肝细胞癌的研究现状

蔡修成; 李晓东

doi:10.12449/JCH251131

中医药调控Hedgehog信号通路防治肝细胞癌的研究现状

DOI: 10.12449/JCH251131

蔡修成¹,
李晓东^{1, 2, 3, , ,}

1.
湖北中医药大学中医学院，武汉 430061
2.
湖北省中医院肝病研究所，中医肝肾研究及应用湖北省重点实验室，武汉 430061
3.
湖北时珍实验室，武汉 430061

基金项目:

湖北省公共卫生领军人才培养计划 (E Wei Tong ［2021］ No. 73);

湖北省自然科学基金 (2024AFD337)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：蔡修成负责课题设计，资料分析，撰写论文；李晓东负责拟定写作思路，指导撰写文章并定稿。

详细信息

通信作者:
李晓东， lixiaodong555@126.com （ORCID： 0000-0002-6406-9416）

计量
- 文章访问数: 4
- HTML全文浏览量: 0
- PDF下载量: 3
- 被引次数: 0
出版历程
- 收稿日期: 2025-03-01
- 录用日期: 2025-05-06
- 出版日期: 2025-11-25

Current status of research on traditional Chinese medicine regulating the Hedgehog signaling pathway for prevention and treatment of hepatocellular carcinoma

Xiucheng CAI¹,
Xiaodong LI^{1, 2, 3
, ,
,}

1.
College of Traditional Chinese Medicine，Hubei University of Chinese Medicine，Wuhan 430061，China
2.
Institute of Liver Diseases，Hubei Key Laboratory of Theoretical and Applied Research of Liver and Kidney in Traditional Chinese Medicine，Hubei Provincial Hospital of Traditional Chinese Medicine，Wuhan 430061，China
3.
Hubei Shizhen Laboratory，Wuhan 430061，China

Research funding:

Hubei Province Public Health Leading Talent Training Program (E Wei Tong ［2021］ No. 73);

Natural Science Foundation of Hubei Province (2024AFD337)

More Information

Corresponding author: LI Xiaodong， lixiaodong555@126.com （ORCID： 0000-0002-6406-9416）

摘要

摘要: 肝细胞癌（HCC）的发病机制涉及慢性肝损伤引发的炎症与肝纤维化，导致肝干细胞异常增殖及变异，形成肿瘤细胞。虽然HCC的西医疗法取得了较大进展，但患者5年生存率不足20%，且面临耐药性强、不良反应等局限性。近年来，中医药以其多成分、多靶点调控肿瘤微环境及信号通路的独特优势，在抗肿瘤领域的应用逐渐受到重视。Hedgehog信号通路在细胞增殖、分化及肿瘤转移中发挥重要作用，其在肝癌发生发展中的作用日益受到关注。本文综述了中药单体和中药复方靶向调控Hedgehog信号通路发挥抗HCC的机制和研究进展，旨在为中医药防治HCC提供新的思路。
- 癌，肝细胞 /
- 猬蛋白质类 /
- 信号传导 /
- 中医治疗学
Abstract: The pathogenesis of hepatocellular carcinoma （HCC） involves inflammation and liver fibrosis caused by chronic liver injury， leading to the abnormal proliferation and mutation of liver stem cells and the formation of tumor cells. Although great progress has been made in Western medicine treatment of HCC， the 5-year survival rate of patients remains below 20%， with the limitations such as strong drug resistance and adverse reactions. In recent years， traditional Chinese medicine （TCM） has gradually gained attention in the field of antitumor therapy due to its unique advantages of regulating tumor microenvironment and signaling pathways through multiple components and targets. The Hedgehog signaling pathway plays an important role in cell proliferation， differentiation， and tumor metastasis， and its role in the development and progression of liver cancer has attracted more and more attention. This article reviews the mechanisms and research advances in the anti-HCC effect of TCM monomers and compound prescriptions through targeted regulation of the Hedgehog signaling pathway， in order to provide new ideas for TCM prevention and treatment of HCC.
- Carcinoma，Hepatocellular /
- Hedgehog Proteins /
- Signal Transduction /
- Therapeutics （TCM）

HTML全文

注： EMT，上皮-间充质转化。

图 1 中医药靶向Hh信号通路调控HCC的机制

Figure 1. Traditional Chinese medicine targeting Hh to regulate hepatocellular carcinoma

下载: 全尺寸图片幻灯片

表 1 中医药调控Hh信号通路防治HCC的机制

Table 1. Mechanism of traditional Chinese medicine regulating hedgehog signaling pathway in preventing and treating HCC

中药单体和复方	模型	剂量	作用靶点	作用	参考文献
茶黄素	肝癌HepG2细胞	20、40、80 μmol/L	抑制Hh/SMO、Wnt/β-catenin通路	抑制肿瘤细胞增殖，诱导凋亡	［28］
千层纸素A	HepG2/MHCC97-L、 Bel-7402、HCCLM3、 Huh7、SMMC-7721 及HUVEC细胞	0、2.5、5、10、20、40、80、 100 μmol/L	抑制P4HB/Hh通路	抑制肝癌细胞血管新生	［31］
虫草素	Huh7、HepG2及 SMMC-7721细胞系	40、80、120 μmol/L	抑制Hh/Gli1	抑制肝癌细胞聚集、增殖，并促进其凋亡	［33］
蝙蝠葛碱	Huh7细胞	2、4、8 μg/mL	抑制Hh/Bcl2	促进肝癌细胞凋亡	［36］
悬钩子碱	HepG2细胞	0、0.25、0.5 mg/mL	抑制SHh/PTCH/Gli1/SMO	抑制肝肿瘤细胞迁移和侵袭	［38］
柴胡皂苷	Hep3B细胞	0、2、4、6、10、15 μmol/L	抑制SHh/Gli1/SMO	抑制肝Hep3B细胞生长，提高化疗敏感性	［40］
白杨素	SMMC-7721细胞系	5、10、20 μmol/L	抑制Hh/Gli1/SMO	抑制人肝癌细胞 SMMC-7721肝癌干细胞特性	［42］
麦冬皂苷B	HepG2/ADM	5、10、20、40、80 μmol/L	抑制SHh/Gli1	抑制肝癌细胞的增殖、迁移与侵袭，提高对 ADM的敏感性	［44］
益母草碱	人肝癌细胞株 SMMC-7721	10、20、30 μg/mL	抑制SHh/Gli1/SMO	抑制肝癌细胞增殖和血管生成	［46］
复方叶下珠	HepG2细胞	2、4、6 μg/mL	抑制SHh/PTCH/Gli1	抑制HCC的体外增殖和迁移	［48］
槲芪散	HCC大鼠	5 mmol/L	抑制Hh/Cyclin D/Cyclin E	促进肝癌细胞凋亡	［50］
消癌平	Hep3B的肝癌裸鼠皮下移植瘤模型	100 mg/kg	抑制Hh/Gli1、Hippo信号通路、 Wnt信号通路	抑制肝癌干性	［51］
蟾蜍灵	HCC-LM3细胞	0.04、0.214、0.412 μg/mL	抑制SHh/PTCH1/Gli1/MMP-2、 MMP-9、β-catenin、VEGF	抑制上皮间质转化和血管新生	［52］
注：HUVEC，人脐静脉内皮细胞；ADM，阿霉素。

下载: 导出CSV

参考文献(52)

[1]	WANG WY, WEI C. Advances in the early diagnosis of hepatocellular carcinoma[J]. Genes Dis, 2020, 7( 3): 308- 319. DOI: 10.1016/j.gendis.2020.01.014.
[2]	BROZZETTI S, BEZZI M, de SANCTIS GM, et al. Elderly and very elderly patients with hepatocellular carcinoma. Strategy for a first line treatment[J]. Ann Ital Chir, 2014, 85( 2): 120- 128.
[3]	RAMANI A, TAPPER EB, GRIFFIN C, et al. Hepatocellular carcinoma-related mortality in the USA, 1999-2018[J]. Dig Dis Sci, 2022, 67( 8): 4100- 4111. DOI: 10.1007/s10620-022-07433-8.
[4]	HAO XP, SUN GS, ZHANG Y, et al. Targeting immune cells in the tumor microenvironment of HCC: New opportunities and challenges[J]. Front Cell Dev Biol, 2021, 9: 775462. DOI: 10.3389/fcell.2021.775462.
[5]	KATO A, MIYAZAKI M, AMBIRU S, et al. Multidrug resistance gene(MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection[J]. J Surg Oncol, 2001, 78( 2): 110- 115. DOI: 10.1002/jso.1129.
[6]	LONG LJ, WANG ZY, ZHAO YL, et al. Research advances in traditional Chinese medicine for the treatment of hepatocellular carcinoma by regulating immune cells[J]. J Clin Hepatol, 2025, 41( 2): 349- 358. DOI: 10.12449/JCH250223. 龙丽娟, 王宗玉, 赵雅丽, 等. 中药调控免疫细胞治疗肝细胞癌的研究进展[J]. 临床肝胆病杂志, 2025, 41( 2): 349- 358. DOI: 10.12449/JCH250223.
[7]	LI QJ, WAN LJ, LYU L. Effects of compound Mylabris capsule on proliferation, apoptosis, migration and invasion of colon cancer cells by regulating Wnt/β-catenin signaling pathway[J]. Chin J Gerontol, 2024, 44( 11): 2768- 2773. 李秋菊, 万丽剑, 吕雷. 复方斑蝥胶囊调节Wnt/β-Catenin信号通路对结肠癌细胞增殖、凋亡、迁移和侵袭的影响[J]. 中国老年学杂志, 2024, 44( 11): 2768- 2773.
[8]	LUO XM, ZENG XM, CAI LR, et al. Effects of celastrol on drug resistance of liver cancer cells through FAK/MEK/ERK signaling pathway[J]. China Pharm, 2024, 35( 20): 2477- 2481. DOI: 10.6039/j.issn.1001-0408.2024.20.06. 罗晓明, 曾贤敏, 蔡良韧, 等. 雷公藤红素通过FAK/MEK/ERK信号通路对肝癌细胞耐药性的影响[J]. 中国药房, 2024, 35( 20): 2477- 2481. DOI: 10.6039/j.issn.1001-0408.2024.20.06.
[9]	ZHANG XW, DENG X, CHEN ZS, et al. Research progress on the potential mechanism of Lingzhi(Ganoderma) in hepatic carcinoma treating[J]. J Liaoning Univ Tradit Chin Med, 2025, 27( 8): 77- 82. DOI: 10.13194/j.issn.1673-842X.2025.08.015. 张雪巍, 邓鑫, 陈泽山, 等. 灵芝治疗肝癌潜在作用机制研究进展[J]. 辽宁中医药大学学报, 2025, 27( 8): 77- 82. DOI: 10.13194/j.issn.1673-842X.2025.08.015.
[10]	ZHANG R, REN QW, WEI PF, et al. Study on Taipei Fritillary Bulb on the inhibition of proliferation and migration of liver cancer cell through PI3K/AKT signaling pathway[J]. J Changchun Univ Chin Med, 2025, 41( 6): 634- 639. DOI: 10.13463/j.cnki.cczyy.2025.06.010. 张睿, 任清维, 卫培峰, 等. 太白贝母调控PI3K/AKT通路抑制肝癌细胞增殖与迁移[J]. 长春中医药大学学报, 2025, 41( 6): 634- 639. DOI: 10.13463/j.cnki.cczyy.2025.06.010.
[11]	CHEN SS, ZHOU BH, HUANG W, et al. The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression[J]. Cell Death Dis, 2023, 14( 12): 830. DOI: 10.1038/s41419-023-06358-y.
[12]	NAGASE T, NAGASE M, MACHIDA M, et al. Hedgehog signaling: A biophysical or biomechanical modulator in embryonic development[J]. Ann N Y Acad Sci, 2007, 1101: 412- 438. DOI: 10.1196/annals.1389.029.
[13]	ABRAMYAN J. Hedgehog signaling and embryonic craniofacial disorders[J]. J Dev Biol, 2019, 7( 2): 9. DOI: 10.3390/jdb7020009.
[14]	LIM S, LIM SM, KIM MJ, et al. Sonic hedgehog pathway as the prognostic marker in patients with extensive stage small cell lung cancer[J]. Yonsei Med J, 2019, 60( 10): 898- 904. DOI: 10.3349/ymj.2019.60.898.
[15]	LI QY, ZHANG Y, ZHAN HF, et al. The Hedgehog signalling pathway and its prognostic impact in human gliomas[J]. ANZ J Surg, 2011, 81( 6): 440- 445. DOI: 10.1111/j.1445-2197.2010.05585.x.
[16]	EFRONI S, MEERZAMAN D, SCHAEFER CF, et al. Systems analysis utilising pathway interactions identifies sonic hedgehog pathway as a primary biomarker and oncogenic target in hepatocellular carcinoma[J]. IET Syst Biol, 2013, 7( 6): 243- 251. DOI: 10.1049/iet-syb.2010.0078.
[17]	CHEN XL, LINGALA S, KHOOBYARI S, et al. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations[J]. J Hepatol, 2011, 55( 4): 838- 845. DOI: 10.1016/j.jhep.2010.12.043.
[18]	NOMAN AS, UDDIN M, CHOWDHURY AA, et al. Serum sonic hedgehog(SHH) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer[J]. Sci Rep, 2017, 7( 1): 1796. DOI: 10.1038/s41598-017-01268-4.
[19]	LIU ZK, TU KS, WANG YF, et al. Hypoxia accelerates aggressiveness of hepatocellular carcinoma cells involving oxidative stress, epithelial-mesenchymal transition and non-canonical hedgehog signaling[J]. Cell Physiol Biochem, 2017, 44( 5): 1856- 1868. DOI: 10.1159/000485821.
[20]	de REYNIÈS A, JAVELAUD D, ELAROUCI N, et al. Large-scale pan-cancer analysis reveals broad prognostic association between TGF-β ligands, not Hedgehog, and GLI1/2 expression in tumors[J]. Sci Rep, 2020, 10( 1): 14491. DOI: 10.1038/s41598-020-71559-w.
[21]	FAN YH, DING J, NGUYEN S, et al. Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells[J]. Oncogene, 2016, 35( 1): 116- 124. DOI: 10.1038/onc.2015.67.
[22]	DING J, LI HY, ZHANG L, et al. Hedgehog signaling, a critical pathway governing the development and progression of hepatocellular carcinoma[J]. Cells, 2021, 10( 1): 123. DOI: 10.3390/cells10010123.
[23]	MACHADO MV, DIEHL AM. Hedgehog signalling in liver pathophysiology[J]. J Hepatol, 2018, 68( 3): 550- 562. DOI: 10.1016/j.jhep.2017.10.017.
[24]	ZHANG ZR, YANG JY, LIU R, et al. Inhibiting HMGCR represses stemness and metastasis of hepatocellular carcinoma via Hedgehog signaling[J]. Genes Dis, 2024, 11( 5): 101285. DOI: 10.1016/j.gendis.2024.101285.
[25]	LEE TK, GUAN XY, MA S. Cancer stem cells in hepatocellular carcinoma: From origin to clinical implications[J]. Nat Rev Gastroenterol Hepatol, 2022, 19( 1): 26- 44. DOI: 10.1038/s41575-021-00508-3.
[26]	IKEDA M, MORIZANE C, UENO M, et al. Chemotherapy for hepatocellular carcinoma: Current status and future perspectives[J]. Jpn J Clin Oncol, 2018, 48( 2): 103- 114. DOI: 10.1093/jjco/hyx180.
[27]	ZHANG X, YIN JL, WANG JX, et al. Research progress on anti-tumor mechanism of theaflavins natural products[J]. Cancer Res Prev Treat, 2022, 49( 8): 820- 826. DOI: 10.3971/j.issn.1000-8578.2022.21.1292. 张雪, 尹君丽, 王稼祥, 等. 茶黄素类天然产物抗肿瘤机制的研究进展[J]. 肿瘤防治研究, 2022, 49( 8): 820- 826. DOI: 10.3971/j.issn.1000-8578.2022.21.1292.
[28]	GUO YM, SU YY, LIU SP, et al. Effects of theaflavins on HepG2 cell proliferation and apoptosis by regulating Wnt/β-catenin and Hedgehog signaling pathway[J]. J Guangdong Pharm Univ, 2024, 40( 1): 73- 77. DOI: 10.16809/j.cnki.2096-3653.2023090401. 郭永木, 苏亚勇, 刘双平, 等. 茶黄素通过调节Wnt/β-catenin和Hedgehog信号通路对HepG2细胞增殖和凋亡的影响[J]. 广东药科大学学报, 2024, 40( 1): 73- 77. DOI: 10.16809/j.cnki.2096-3653.2023090401.
[29]	KAI J, YANG X, WANG ZM, et al. Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease[J]. Free Radic Biol Med, 2020, 153: 89- 102. DOI: 10.1016/j.freeradbiomed.2020.03.031.
[30]	WEI LB, DAI YY, ZHOU YX, et al. Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block cancer progression[J]. Cell Death Dis, 2017, 8( 7): e2944. DOI: 10.1038/cddis.2017.335.
[31]	ZHOU TT, ZHANG Y, LIU ZG, et al. Oroxylin a inhibiting the tumor angiogenesis of liver cancer by regulating P4HB-mediated hedgehog signal[J]. China Pharm, 2022, 25( 12): 2061- 2067. DOI: 10.19962/j.cnki.issn1008-049X.2022.12.001. 周婷婷, 张燕, 刘兆国, 等. 千层纸素A通过调控P4HB蛋白介导的hedgehog信号抑制肝癌血管生成[J]. 中国药师, 2022, 25( 12): 2061- 2067. DOI: 10.19962/j.cnki.issn1008-049X.2022.12.001.
[32]	JIN Y, MENG X, QIU ZD, et al. Anti-tumor and anti-metastatic roles of cordycepin, one bioactive compound of Cordyceps militaris[J]. Saudi J Biol Sci, 2018, 25( 5): 991- 995. DOI: 10.1016/j.sjbs.2018.05.016.
[33]	TONG WX, LUO N, LI GF, et al. Mechanism of cordycepin inhibiting proliferation and promoting apoptosis of hepatoma cells by regulating Gli1[J]. Chin J Exp Tradit Med Formulae, 2022, 28( 2): 104- 111. DOI: 10.13422/j.cnki.syfjx.20220295. 童汪霞, 罗宁, 李桂凤, 等. 虫草素通过调控Gli1介导抗肝癌细胞增殖及促凋亡的机制[J]. 中国实验方剂学杂志, 2022, 28( 2): 104- 111. DOI: 10.13422/j.cnki.syfjx.20220295.
[34]	HAN H, YIN X, ZHANG TY, et al. Research progress of dauricine[J]. Inf Tradit Chin Med, 2014, 31( 2): 111- 114. 韩华, 殷鑫, 张天宇, 等. 蝙蝠葛碱的研究进展[J]. 中医药信息, 2014, 31( 2): 111- 114.
[35]	BIAN WS, ZHANG YB, ZHANG CY, et al. Research status of pharmacological action of dauricine[J]. Heilongjiang Sci, 2014, 5( 7): 10- 11. DOI: 10.3969/j.issn.1674-8646.2014.07.003. 边文山, 张英博, 张朝颖, 等. 蝙蝠葛碱药理作用的研究现状[J]. 黑龙江科学, 2014, 5( 7): 10- 11. DOI: 10.3969/j.issn.1674-8646.2014.07.003.
[36]	ZHU PF, LYU J, LIU YM, et al. Effect and mechanism of dauricine on proliferation and apoptosis of hepatoma Huh7 cells[J]. Chin Tradit Herb Drugs, 2019, 50( 5): 1151- 1156. DOI: 10.7501/j.issn.0253-2670.2019.05.019. 朱鹏飞, 吕君, 刘艳民, 等. 蝙蝠葛碱对肝癌Huh7细胞增殖和凋亡的作用及机制研究[J]. 中草药, 2019, 50( 5): 1151- 1156. DOI: 10.7501/j.issn.0253-2670.2019.05.019.
[37]	ZHAO JY, CHEN XZ, LIN W, et al. Total alkaloids of Rubus aleaefolius Poir inhibit hepatocellular carcinoma growth in vivo and in vitro via activation of mitochondrial-dependent apoptosis[J]. Int J Oncol, 2013, 42( 3): 971- 978. DOI: 10.3892/ijo.2013.1779.
[38]	ZHAO LX, WANG WX. miR-125b suppresses the proliferation of hepatocellular carcinoma cells by targeting Sirtuin7[J]. Int J Clin Exp Med, 2015, 8( 10): 18469- 18475.
[39]	ZHONG D, ZHANG HJ, JIANG YD, et al. Saikosaponin-d: A potential chemotherapeutics in castration resistant prostate cancer by suppressing cancer metastases and cancer stem cell phenotypes[J]. Biochem Biophys Res Commun, 2016, 474( 4): 722- 729. DOI: 10.1016/j.bbrc.2016.05.017.
[40]	ZHANG CY, JIANG ZM, MA XF, et al. Saikosaponin-d inhibits the hepatoma cells and enhances chemosensitivity through SENP5-dependent inhibition of Gli1 SUMOylation under hypoxia[J]. Front Pharmacol, 2019, 10: 1039. DOI: 10.3389/fphar.2019.01039.
[41]	REN KQ, CAO XZ, LIU ZH, et al. 8-bromo-5-hydroxy-7-methoxychrysin targeting for inhibition of the properties of liver cancer stem cells by modulation of Twist signaling[J]. Int J Oncol, 2013, 43( 5): 1719- 1729. DOI: 10.3892/ijo.2013.2071.
[42]	ZHANG YQ, PAN WN, YAN M, et al. Effects of chrysin on expression of CK2α and Gli1 and spheroid formation in liver cancer stem-like cells from SMMC-7721 cell line[J]. Nat Prod Res Dev, 2017, 29( 12): 2117- 2121, 2086. DOI: 10.16333/j.1001-6880.2017.12.020. 张燕琴, 潘伟男, 阎敏, 等. 白杨素对肝癌干样细胞球形成及CK2α和Gli1表达的影响[J]. 天然产物研究与开发, 2017, 29( 12): 2117- 2121, 2086. DOI: 10.16333/j.1001-6880.2017.12.020.
[43]	HE BQ, ZHOU XJ, SHI DL, et al. Research progress on antitumor mechanism of Ophiopogon japonicus saponin B[J]. Chin Arch Tradit Chin Med, 2018, 36( 12): 2911- 2914. DOI: 10.13193/j.issn.1673-7717.2018.12.022. 何冰倩, 周小杰, 史冬玲, 等. 麦冬皂苷B抗肿瘤作用机制研究进展[J]. 中华中医药学刊, 2018, 36( 12): 2911- 2914. DOI: 10.13193/j.issn.1673-7717.2018.12.022.
[44]	AN Q, QI GZ, HAN C. Effects of ophiopogonin B on regulation of sonic hedgehog/glioma associated oncogene homolog 1 pathway on epithelial mesenchymal transformation and drug resistance in hepatocellular carcinoma[J]. World Clin Drug, 2024, 45( 3): 285- 293. DOI: 10.13683/j.wph.2024.03.008. 安琪, 齐光照, 韩超. 麦冬皂苷B调节Shh/Gli1通路对肝细胞癌上皮间质转化及耐药性的影响[J]. 世界临床药物, 2024, 45( 3): 285- 293. DOI: 10.13683/j.wph.2024.03.008.
[45]	JUNG YY, KIM C, SHANMUGAM MK, et al. Leonurine ameliorates the STAT3 pathway through the upregulation of SHP-1 to retard the growth of hepatocellular carcinoma cells[J]. Cell Signal, 2024, 114: 111003. DOI: 10.1016/j.cellsig.2023.111003.
[46]	WANG J, LYU XM, QI LT. Impacts of leonurine on the proliferation, apoptosis and angiogenesis of hepatoma SMC-7721 cells by regulating shh/Gli1 signaling pathway[J]. Chin J Cell Biol, 2023, 45( 10): 1493- 1500. DOI: 10.11844/cjcb.2023.10.0007. 王健, 吕雪梅, 亓立廷. 益母草碱调节Shh/Gli1信号通路对肝癌SMC-7721细胞增殖、凋亡和血管生成的影响[J]. 中国细胞生物学学报, 2023, 45( 10): 1493- 1500. DOI: 10.11844/cjcb.2023.10.0007.
[47]	TONG GD, ZHANG X, ZHOU DQ, et al. Efficacy of early treatment on 52 patients with preneoplastic hepatitis B virus-associated hepatocellular carcinoma by compound Phyllanthus urinaria L[J]. Chin J Integr Med, 2014, 20( 4): 263- 271. DOI: 10.1007/s11655-013-1320-7.
[48]	LI Y. The study of compound phyllanthus urinaria inhibits HBV related HCC through inactivation Hedgehog pathway[D] Guangzhou: Guangzhou University of Chinese Medicine, 2020. 栗昀. 复方叶下珠抑制Hedgehog信号通路发挥抗HBV相关HCC作用的实验研究[D]. 广州: 广州中医药大学, 2020.
[49]	DONG K, FENG P, JIANG Y, et al. Effects of mistletoe alkali and mistletoe polysaccharose proliferation and apoptosis of hepato carcinoma cells[J]. J Cap Med Univ, 2009, 30( 1): 80- 84. DOI: 10.3969/j.issn.1006-7795.2009.01.020. 董坤, 丰平, 江瑛, 等. 槲寄生碱和多糖对肝癌细胞增生和凋亡的影响[J]. 首都医科大学学报, 2009, 30( 1): 80- 84. DOI: 10.3969/j.issn.1006-7795.2009.01.020.
[50]	LI RF, BAI YF, WANG YJ, et al. Huqi San inhibits prehepatocarcinoma in rats probably through activating Hedgehog signaling pathway[J]. Chin J Pathophysiol, 2017, 33( 4): 661- 668. DOI: 10.3969/j.issn.1000-4718.2017.04.014. 李若菲, 白云飞, 王芸姣, 等. 槲芪散可通过激活Hedgehog信号通路抑制大鼠肝癌前病变的形成[J]. 中国病理生理杂志, 2017, 33( 4): 661- 668. DOI: 10.3969/j.issn.1000-4718.2017.04.014.
[51]	ZHAN J. Preliminary study on the regulation of Xiaoaiping on the stem characteristics of hepatocellular carcinoma and related pathways[D]. Wuhan: Huazhong University of Science and Technology, 2020. 占静. 消癌平对肝癌组织“干性”特征的调控作用及相关通路的初步研究[D]. 武汉: 华中科技大学, 2020.
[52]	SHENG X, SUN XT, SUN K, et al. Inhibitory effect of bufalin combined with Hedgehog signaling pathway inhibitors on proliferation and invasion and metastasis of liver cancer cells[J]. Int J Oncol, 2016, 49( 4): 1513- 1524. DOI: 10.3892/ijo.2016.3667.