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Sorafenib attenuated the function of natural killer cells infiltrated in HCC through inhibiting ERK1/2

机译:Sorafenib通过抑制ERK1 / 2抑制了HCC中渗透渗透的天然杀手细胞的功能

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摘要

Sorafenib has been systemically utilized to therapy the advanced hepatocellular carcinoma (HCC). Natural killer cells (NKs) are important cytotoxic innate lymphocytes, which can exert effector functions especially in liver and tumor. However, how Sorafenib affects the function of NKs remains to be elucidated. Here, we utilized the subcutaneous and in situ tumor bearing mice with mouse hepatoma cell line hepa 1-6. At the endpoint, the number and function of NKs in blood, liver, TDLN, and tumor were explored using FACS, ELISA, WB, etc. To confirm the direct effects of Sorafenib on NKs, the NKs were sorted using FACS, which were then stimulated with Sorafenib to detect the functions and the relevant mechanisms using qPCR, western blot, and FACS in vitro. Finally, we found that Sorafenib led to a significant block of tumor progression, but reduced the number of NK cells through suppressing the proliferation of NK cells. This phenotype made us study the terminal function of NK cells, revealing that Sorafenib could decrease the production of effector molecules and cytokines, such as perforin, granzyme B, TNF-alpha, IFN-gamma, etc. Besides, p-ERK1/2 in NK cells was inhibited after treatment with Sorafenib, and a similar tendency of NK cells could be achieved using ERK1/2 inhibitor. Collectively, our data suggested that Sorafenib functioned as a critical inhibitor that controlled the number and function of NK cells through inhibiting ERK1/2.
机译:Sorafenib已系统性地用于治疗晚期肝细胞癌(HCC)。天然杀手细胞(NKS)是重要的细胞毒性先天淋巴细胞,其可以施加效应器功能,特别是在肝脏和肿瘤中。然而,索拉非尼影响NKS的功能仍然阐明。在这里,我们利用皮下和原位肿瘤轴承小鼠与小鼠肝癌细胞系HEPA 1-6。在终点,使用FACS,ELISA,WB等探索血液,肝脏,TDLN和肿瘤中NKS的数量和功能,以确认Sorafenib对NKS的直接影响,使用FACS对NKS进行分类用索拉非尼刺激以检测使用QPCR,Western印迹和体外FACS的功能和相关机制。最后,我们发现Sorafenib导致了大量的肿瘤进展,但通过抑制NK细胞的增殖来降低NK细胞的数量。该表型使我们研究了NK细胞的末端功能,揭示了索拉非尼可以降低效应分子和细胞因子的产生,例如穿孔素,颗粒酶B,TNF-α,IFN-γ等。(P-ERK1 / 2)在用索拉非尼处理后抑制NK细胞,并且可以使用ERK1 / 2抑制剂实现类似的NK细胞的趋势。统称,我们的数据表明Sorafenib用作通过抑制ERK1 / 2控制NK细胞的数量和功能的关键抑制剂。

著录项

  • 来源
    《International immunopharmacology》 |2019年第2019期|共6页
  • 作者单位

    Peking Univ Dept Radiat Oncol Hosp 3 Beijing 100191 Peoples R China;

    Peking Univ Dept Radiat Oncol Hosp 3 Beijing 100191 Peoples R China;

    Peking Univ Ctr Reprod Med Dept Obstet &

    Gynecol Hosp 3 Beijing 100191 Peoples R China;

    Peking Univ Dept Radiat Oncol Hosp 3 Beijing 100191 Peoples R China;

    Peking Univ Dept Radiat Oncol Hosp 3 Beijing 100191 Peoples R China;

    Peking Univ Dept Radiat Oncol Hosp 3 Beijing 100191 Peoples R China;

    Peking Univ Dept Radiat Oncol Hosp 3 Beijing 100191 Peoples R China;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    Sorafenib; NKs; Natural killer cell; HCC;

    机译:索拉非尼;NKS;天然杀手细胞;HCC;

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