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首页> 外文期刊>Molecular Carcinogenesis >Epidermal growth factor induces STAT1 expression to exacerbate the IFNr-mediated PD-L1 axis in epidermal growth factor receptor-positive cancers
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Epidermal growth factor induces STAT1 expression to exacerbate the IFNr-mediated PD-L1 axis in epidermal growth factor receptor-positive cancers

机译：表皮生长因子诱导STAT1表达，使IFNR介导的IFNR介导的PD-L1轴加剧表皮生长因子受体阳性癌症中的IFNR介导的PD-L1轴

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摘要

The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.
机译：在许多癌症中过表达的表皮生长因子（EGF）受体（EGFR），包括肺和头部和颈部癌症，并参与癌细胞进展和存活。 PD-L1，肿瘤细胞增加，抑制CD8 + T细胞，是临床免疫治疗靶标。该研究研究了EGF对EGFR阳性癌症中的调节PD-L1的分子机制，并确定了降低PD-L1表达的潜在试剂。进行RNA测序（RNA淀酶）和生物信息学分析以确定调节肿瘤细胞中PD-L1的潜在驾驶员基因 - 衍生的肿瘤细胞，其模仿癌症干细胞。然后，施用靶向EGFR的特异性抑制剂以减少体外和体内PD-L1的表达。我们验证了EGF可以在所选EGFR阳性癌症中诱导PD-L1表达。 RNASEQ结果表明，STAT1随着KOSC-3衍生的肿瘤球中的驾驶员基因增加;使用Panther进行分析这些数据，然后进行NetworkAnalyst。 AFATINIB的EGFR阻断导致STAT1和IRF-1水平降低，两者都是PD-L1的转录因子，并在体外和体内禁用IFNR-Stat1介导的PD-L1轴。此外，STAT1敲低显着减少了EGF介导的PD-L1表达，ruxolitinib，JAK1 / JAK2抑制剂，显着抑制Stat1磷酸化以减少IFNR介导的PD-L1轴。这些结果表明，通过增加STAT1的蛋白质水平来强化PD-L1，以在所选EGFR阳性癌症中强化IFNR-JAK1 / 2介导的信号传导轴。 AFATINIB对EGFR的抑制显着降低了PD-L1，并且可以是提高免疫治疗效果的潜在策略。

著录项

  • 来源
    《Molecular Carcinogenesis》 |2018年第11期|共11页
  • 作者

    Cheng Chun-Chia; Lin Hsin-Chi; Tsai Kaun-Jer; Chiang Ya-Wen; Lim Ken-Hong; Chen Caleb Gon-Shen; Su Ying-Wen; Peng Cheng-Liang; Ho Ai-Sheng; Huang Ling; Chang Yu-Cheng; Lin Huan-Chau; Chang Jungshan; Chang Yi-Fang;

  • 作者单位

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    Cheng Hsin Gen Hosp Div Gastroenterol Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    Atom Energy Council Inst Nucl Energy Res Taoyuan Taiwan;

    Cheng Hsin Gen Hosp Div Gastroenterol Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

    Taipei Med Univ Grad Inst Med Sci Sch Med Coll Med Taipei Taiwan;

    MacKay Mem Hosp Div Hematol &

    Oncol Dept Internal Med Taipei Taiwan;

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

    afatinib; EGFR; lung cancer; PD-L1; STAT1;

    机译：Deadinib;EGFR;肺癌;PD-L1;Stat1;

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