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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis
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Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis

机译：酪氨酸激酶Syk是肝纤维化的潜在治疗靶标

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摘要

Spleen tyrosine kinase (SYK) plays a critical role in immune cell signaling pathways and has been reported as a biomarker for human hepatocellular carcinoma (HCC). We sought to investigate the mechanism by which SYK promotes liver fibrosis and to evaluate SYK as a therapeutic target for liver fibrosis. We evaluated the cellular localization of SYK and the association between SYK expression and liver fibrogenesis in normal, hepatitis B virus (HBV)‐infected, hepatitis C virus (HCV)‐infected and non‐alcoholic steatohepatitis (NASH) liver tissue (n=36, 127, 22 and 30, respectively). A polymerase chain reaction (PCR) array was used to detect the changes in transcription factor (TF) expression in hepatic stellate cells (HSCs) with SYK knockdown. The effects of SYK antagonism on liver fibrogenesis were studied in LX‐2 cells, TWNT‐4 cells, primary human HSCs, and three progressive fibrosis/cirrhosis animal models, including a CCL 4 mouse model, and diethylnitrosamine (DEN) and bile duct ligation (BDL) rat models. We found that SYK protein in HSCs and hepatocytes correlated positively with liver fibrosis stage in human liver tissue. HBV or HCV infection significantly increased SYK and cytokine expression in hepatocytes. Increasing cytokine production further induced SYK expression and fibrosis‐related gene transcription in HSCs. Up‐regulated SYK in HSCs promoted HSC activation by increasing the expression of specific TFs related to activation of HSCs. SYK antagonism effectively suppressed liver fibrosis via inhibition of HSC activation, and decreased obstructive jaundice and reduced HCC development in animal models. Conclusion : SYK promotes liver fibrosis via activation of HSCs and is an attractive potential therapeutic target for liver fibrosis and prevention of HCC development. (H epatology 2018).
机译：脾酪氨酸激酶（SYK）在免疫细胞信号传导通路中起关键作用，并已被报道作为人类肝细胞癌（HCC）的生物标志物。我们试图探讨由SYK促进肝纤维化的机制，以评估SYK为肝纤维化的治疗靶点。我们评估了SYK的细胞定位和SYK表达，在正常肝纤维化之间的关联，乙型肝炎病毒（HBV）感染，丙型肝炎病毒（HCV）感染和非酒精性脂肪性肝炎（NASH）肝组织（n = 36分别127，22和30）。聚合酶链反应（PCR）阵列被用于检测在肝星状细胞（HSC）中，用SYK击倒在转录因子（TF）表达的变化。 SYK拮抗作用对肝纤维化的影响进行了研究在LX-2细胞，TWNT-4细胞，原代人HSCs，和三个进行性纤维化/肝硬化的动物模型，包括CCL 4小鼠模型，和二乙基亚硝胺（DEN）和胆管结扎（BDL）大鼠模型。我们发现，SYK蛋白在造血干细胞和肝细胞在人类肝组织肝纤维化阶段呈正相关。 HBV或HCV感染显著增加SYK和肝细胞中细胞因子的表达。增加细胞因子的产生进一步诱导造血干细胞SYK表达和纤维化有关的基因转录。在造血干细胞上调SYK通过增加相关的造血干细胞的活化转录因子特异性的表达，促进HSC激活。通过抑制HSC活化的拮抗作用SYK有效地抑制肝纤维化，和降低的梗阻性黄疸和在动物模型中减少HCC的发展。结论：SYK促进造血干细胞通过激活肝纤维化是肝纤维化和肝癌的预防发展的一个有吸引力的潜在治疗靶点。 （2018年Hopatology）。

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  • 作者

    Qu Chen; Zheng Dandan; Li Sai; Liu Yingjun; Lidofsky Anna; Holmes Jacinta A.; Chen Jianning; He Lu; Wei Lan; Liao Yadi; Yuan Hui; Jin Qimeng; Lin Zelong; Hu Qiaoting; Jiang Yuchuan; Tu Mengxian; Chen Xijun; Li Weiming; Lin Wenyu; Fuchs Bryan C.; Chung Raymond T.; Hong Jian;

  • 作者单位

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Pharmacy Integrated Hospital of Traditional Chinese MedicineSouthern Medical;

    Department of General SurgeryAffiliated Tumor Hospital of Zhengzhou UniversityZhengzhou China;

    Gastrointestinal Unit Department of Medicine Massachusetts General HospitalHarvard Medical;

    Gastrointestinal Unit Department of Medicine Massachusetts General HospitalHarvard Medical;

    Department of PathologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhou China;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Division of Surgical OncologyMassachusetts General Hospital Cancer Center and Harvard Medical;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

    Gastrointestinal Unit Department of Medicine Massachusetts General HospitalHarvard Medical;

    Division of Surgical OncologyMassachusetts General Hospital Cancer Center and Harvard Medical;

    Gastrointestinal Unit Department of Medicine Massachusetts General HospitalHarvard Medical;

    Department of Abdominal Surgery Integrated Hospital of Traditional Chinese MedicineSouthern;

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  • 正文语种 eng
  • 中图分类 消化系及腹部疾病;
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