中药调控Janus激酶/信号转导和转录激活因子（JAK/STAT）信号通路防治肝细胞癌的研究现状

杨星; 李淑娣; 刘江凯; 王振; 李素领

doi:10.3969/j.issn.1001-5256.2023.11.030

中药调控Janus激酶/信号转导和转录激活因子（JAK/STAT）信号通路防治肝细胞癌的研究现状

DOI: 10.3969/j.issn.1001-5256.2023.11.030

杨星¹,
李淑娣¹,
刘江凯^2a,
王振^2b,
李素领^2c, , ,

1.
河南中医药大学第一临床医院，郑州 450046
2a.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000
2b.
河南中医药大学第一附属医院科研部，郑州 450000
2c.
河南中医药大学第一附属医院国医堂，郑州 450000

基金项目:

河南省中医管理局科研专项 (20-21ZY1011);

河南省中医管理局科研专项 (2022ZY1002);

河南省中医管理局科研专项 (2022JDZX048)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：杨星负责课题设计，资料收集，分析文献资料，撰写论文；王振、李淑娣负责修改论文；李素领、刘江凯负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
李素领， hk-lsl@163.com （ORCID： 0000-0002-5211-1330）

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出版历程
- 收稿日期: 2023-07-11
- 录用日期: 2023-08-14
- 出版日期: 2023-11-28

Current research status of traditional Chinese medicine in the prevention and treatment of hepatocellular carcinoma by regulating the JAK/STAT signaling pathway

Xing YANG¹,
Shudi LI¹,
Jiangkai LIU^2a,
Zhen WANG^2b,
Suling LI^{2c
, ,
,}

1.
The First Clinical Hospital of Henan University of Chinese Medicine，Zhengzhou 450046，China
2a.
Department of Hepatology and Spleen-Stomach，The First Affiliated Hospital of Henan University of Chinese Medicine，Zhengzhou 450000，China
2b.
Department of Scientific Research，The First Affiliated Hospital of Henan University of Chinese Medicine，Zhengzhou 450000，China
2c.
Chinese Medical Hall，The First Affiliated Hospital of Henan University of Chinese Medicine，Zhengzhou 450000，China

Research funding:

Henan Provincial Administration of Traditional Chinese Medicine Research Project (20-21ZY1011);

Scientific Research Project of Henan Provincial Administration of Traditional Chinese Medicine (2022ZY1002);

Henan Provincial Administration of Traditional Chinese Medicine Research Project (2022JDZX048)

More Information

Corresponding author: LI Suling， hk-lsl@163.com （ORCID： 0000-0002-5211-1330）

摘要

摘要: 肝细胞癌（HCC）是常见的消化道恶性肿瘤之一，因发病率高、恶性程度高、强侵袭与转移、预后差，严重威胁患者生命。目前HCC的主要防治手段有药物、手术及介入治疗等，但均存在一定的不良反应及副作用。Janus激酶/信号转导和转录活化因子（JAK/STAT）作为人体重要的细胞内信号转导通路，其主要通过调控细胞侵袭、转移、增殖、生长、凋亡、自噬、血管生成、炎症/免疫反应、铁代谢和药物耐药性等方面，发挥抗肝细胞癌效应。因此，靶向JAK/STAT信号通路对防治肝细胞癌的发生发展具有重要作用。中医药在HCC的治疗上具有多靶点、多途径、多成分、多层次的优势受到广泛关注，大量中医药治疗HCC的细胞或动物实验表明JAK/STAT信号通路是防治HCC的重要靶点，具有改善肝功能、减少HCC复发和提高免疫力等作用。基于此，本文通过梳理JAK/STAT信号通路在肝细胞癌中的作用机制，以及中药单体、中药提取物和中药复方对JAK/STAT信号通路的干预作用，以期为中医药防治肝细胞癌和临床新药研发给予理论依据和参考。
- 癌，肝细胞 /
- 中草药 /
- 信号传导
Abstract: Hepatocellular carcinoma （HCC） is one of the common malignant tumors of the digestive tract and seriously threatens the life of patients due to a high incidence rate， a high degree of malignancy， strong invasion and metastasis， and poor prognosis. At present， the main methods for the prevention and treatment of HCC include drugs， surgery， and interventional treatment， but all of these methods have certain adverse reactions and side effects. As an important intracellular signal transduction pathway in the human body， the JAK/STAT signaling pathway mainly exerts an anti-HCC effect by regulating cell invasion， metastasis， proliferation， growth， apoptosis， autophagy， angiogenesis， inflammation/immune response， iron metabolism， and drug resistance. Therefore， targeting the JAK/STAT signaling pathway plays an important role in the prevention and treatment of the development and progression of HCC. Traditional Chinese medicine has attracted wide attention due to its advantages of multiple targets， pathways， components， and levels in the treatment of HCC， and many cell or animal experiments on traditional Chinese medicine in the treatment of HCC have shown that the JAK/STAT signaling pathway is an important target for the prevention and treatment of HCC， with the effects of improving liver function， reducing HCC recurrence， and improving immunity. Based on this， this article analyzes the mechanism of action of the JAK/STAT signaling pathway in HCC， as well as the intervention effect of traditional Chinese medicine monomers， traditional Chinese medicine extracts， and traditional Chinese medicine compounds on the JAK/STAT signaling pathway， in order to provide theoretical basis and reference for the prevention and treatment of HCC and the research and development of new traditional Chinese medicine drugs.
- Carcinoma， Hepatocellular /
- Drugs， Chinese Herbal /
- Signal Transduction

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表 1 中药活性成分及提取物靶向JAK/STAT信号通路调控HCC的作用机制

Table 1. The mechanism of action of traditional Chinese medicine active ingredients and extracts targeting the JAK/STAT signaling pathway to regulate HCC

类别	中药提取物	剂量	干预对象	作用机制	作用结果	参考文献
黄酮类	野黄芩苷	0.01、0.02、0.04 g/L	MHCC97-H和HepG2细胞	上调p-JAK2、p-STAT3、JAK2和STAT3的mRNA，上调E-钙黏蛋白	抑制肝癌细胞增殖和侵袭	［43］
	马鞭草总黄酮	50、100、200 mg/L	HepG2细胞	下调IL-6、p-JAK2、p-STAT3 mRNA和JAK2、STAT3蛋白表达	抑制肝癌细胞增殖	［44］
	荔枝核总黄酮	70、140、210 mg/L	HepG2细胞	上调SHP-1和E-钙黏蛋白，下调JAK2、STAT3磷酸化和Vimentin	抑制肝癌细胞的增殖、迁移和侵袭，促进其凋亡	［45］
	黑枸杞花青素	200 μg/mL	HepG2细胞	下调JAK2、STAT3 mRNA和蛋白表达，上调LC3 基因和LC3-Ⅱ蛋白表达	促进肝癌细胞凋亡并增强细胞自噬	［46］
多糖类	黄芪多糖	200、300、400 mg/L	SMMC-7721细胞	下调p-STAT3/STAT3和p-STAT5/STAT5的蛋白表达	抑制肝癌细胞迁移和侵袭	［47］
	蒲公英多糖	24、48、72、96 mg/L	HepG2和Huh7细胞	下调p-JAK2和p-STAT3以及铁调素的表达	调节肝癌细胞和移植肿瘤中的铁负荷	［48］
	南瓜多糖	0.25、0.5、1.0 mg/kg	HepG3细胞	下调STAT2、STAT3磷酸化和JAK活性	促进肝癌细胞凋亡	［49］
	海参多糖	0、50、100、200 μg/mL	HepG2细胞	下调JAK2、STAT3和survivin及其磷酸化水平	抑制肝癌细胞增殖，促进其凋亡	［50］
萜类	葫芦素E	0、10、20、40 nmol/L	Huh7细胞	下调p-JAK3/JAK3、p-STAT3/STAT3比值及STAT3磷酸化和核易位	抑制肝癌细胞活力、增殖，诱导细胞周期停滞	［20］
	葫芦素I	0.05、0.1、0.5、1.5 μmol/L	HepG2细胞	下调STAT3和JAK2磷酸化水平，下调JAK2和STAT3基因的表达	抑制肝癌细胞活力、增殖。诱导细胞周期停滞	［51］
	斑蝥素	0.1、0.2、0.4 mg/kg	HepG2细胞	下调JAK2、STAT3磷酸化和STAT的核易位水平，下调EphB4的表达	抑制肝癌细胞生长，诱导细胞凋亡	［52］
	苍耳亭	0、1、2.5、5、10、20 μmol/L	HEK293和HepG2细胞	下调JAK1、TYK2和STAT3的磷酸化	抑制肝癌细胞生长	［53］
	隐丹参酮	0.312 5、0.625、1.25、2.5、5、10、20 μg/mL	Hepa1-6细胞系和EG7胸腺瘤细胞系	下调STAT3磷酸化和JAK2活性	抑制肝癌细胞增殖，促进其凋亡	［54］
	青蒿素	100 mg/kg	C57BL/6J小鼠	下调JAK2、STAT3磷酸化和Caspase-3表达	促进肝癌细胞凋亡	［55］
酚类	姜黄素	25 mg·kg·^-1d^-1	H22细胞	下调p-JAK1/2、p-STAT3蛋白和IL-6表达，上调抗炎细胞因子IL-4表达	抑制肝癌细胞生长和EMT，激活宿主免疫反应	［57］
酚类	丹皮酚	7.5、15、22.5、30、60 mg/L	HepG2细胞	下调JAK1，JAK2，STAT3，STAT5蛋白表达	抑制肝癌细胞增殖，促进其凋亡	［58］
生物碱	荷包牡丹碱	5、10、25 μmol/L	MHCC97-H细胞	下调VEGF、MMP-2、MMP-9基因表达及p-JAK2、p-STAT3蛋白表达	抑制肝癌细胞转移和侵袭	［59］
生物碱	氧化槐果碱	2、4、8、16、32 mmol/L	SMMC-7721细胞	下调STAT3、STAT5表达和抗凋亡Bal-2基因表达，上调促凋亡Bax基因表达	抑制肝癌细胞增殖，促进其凋亡	［60］
其他类	白花丹醌	0、1、2、4、8、10 μmol/L	Huh-7和LM3细胞	下调N-钙黏蛋白、MMP-2、JAK和STAT蛋白表达，上调E-钙黏蛋白表达	抑制肝癌细胞的侵袭和迁移	［61］
	蛇床子素	40、80、160 μmol/L	HepG2细胞	下调N-钙黏蛋白、Vimentin、p-JAK/JAK和p-STAT3/STAT3蛋白表达，上调Bax/Bcl-2、Caspase-3和E-钙黏蛋白表达	抑制肝癌细胞增殖和侵袭，促进细胞凋亡	［62］
	沙蟾毒精	5、10、20、40、80 nmol/L	HepG2细胞	下调肿瘤免疫相关因子IL-8分泌水平，下调p-JAK、p-JAK2、p-STAT3蛋白表达	抑制肝癌细胞增殖，促进其凋亡	［63］
	醉茄素A	2.5、5.0、10.0 μmol/L	HepG2/ADM细胞	下调Bcl-2、p-JAK2和p-STAT3蛋白表达水平，上调Caspase-3蛋白表达	促进肝癌细胞凋亡	［64］
中药提取物	石榴皮提取物	0.5、1、1.5 μg/L	HepG2细胞	下调JAK、STAT2、STAT3，上调PPAR-γ和Caspase-3	促进肝癌细胞凋亡	［65］
	青蒿琥酯	25 mg/kg	雄性Wistar大鼠	下调IL-6、p-JAK2、p-STAT3（pY705）、Bcl-xL和Bcl-2的表达，上调Caspase-3和PARP和SOCS3	抑制肝癌细胞增殖，促进其凋亡	［66］
	去甲斑蝥素	0、30、60、120 µmol/L	HCCLM3和SMMC-7721细胞	下调N-钙黏蛋白、Vimentin、p-JAK2、p-STAT3和TWIET表达，上调E-钙黏蛋白	抑制肝癌细胞EMT	［67］
	苦参素注射液	0.75、1.5、3 mg/mL	人耐顺铂肝癌细胞株HepG2/DDP	下调p-JAK2/JAK2、p-STAT3/STAT3水平	增强顺铂化疗敏感性	［68］

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表 2 中药复方靶向JAK/STAT信号通路调控HCC的作用机制

Table 2. The mechanism of action of traditional Chinese medicine compound targeting JAK/STAT signaling pathway to regulate HCC

中药复方	组成	剂量	干预对象	作用机制	作用结果	参考文献
芪楼丸	黄芪、重楼、女贞子、墨旱莲、莪术、白术等	6.75、13.5、27 g/kg	HepG2细胞	上调Bax、Caspase-3和Caspase-9 的表达，下调Bcl-2、Bcl-2 mRNA表达和JAK2、STAT3、p-JAK2、p-STAT3、STAT5蛋白表达	抑制肝癌细胞增殖，促进其凋亡	［69］
茵陈蒿汤	茵陈、栀子、大黄	12.5、25、50 μg/mL	HepG2细胞	下调p-JAK2、JAK2、p-STAT3和STAT3蛋白，下调Cyclin D1、c-Myc以及抗凋亡相关蛋白Mcl-1、Bcl-XL的表达	抑制肝癌细胞增殖，促进其凋亡	［70］
一贯煎	生地黄、麦冬、北沙参、枸杞、川楝子	11.5、23、46 g·kg·^-1d^-1	H22细胞	下调JAK1、STAT1磷酸化和c-Myc、Bal-2表达，上调p53基因	促进肝癌细胞凋亡	［71］
复方苦参注射液	苦参、白土茯苓	0.1 mg/L	HepG2细胞	下调CyclinD1、c-Myc、Bcl-xL、MMP2、MMP9的表达量，下调p-JAK2及p-STAT3的表达	抑制肝癌细胞增殖和侵袭	［72］

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