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
Current research status of traditional Chinese medicine in the prevention and treatment of hepatocellular carcinoma by regulating the JAK/STAT signaling pathway
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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。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.
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Key words:
- 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] 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] 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] 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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