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首页> 外文期刊>Oncogene >Progranulin promotes Temozolomide resistance of glioblastoma by orchestrating DNA repair and tumor stemness
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Progranulin promotes Temozolomide resistance of glioblastoma by orchestrating DNA repair and tumor stemness

机译：颗粒蛋白原通过协调 DNA 修复和肿瘤干性来促进胶质母细胞瘤的替莫唑胺耐药性

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摘要

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a dismal prognosis. Current therapy of surgical removal combined with Temozolomide (TMZ) and radiation therapy only slightly prolongs the survival of GBM patients. Thus, it is essential to elucidate mechanism underlying its highly malignant properties in order to develop efficacious therapeutic regimens. In this study, we showed that progranulin (PGRN) was overexpressed in most GBM cell lines and the majority of human tumor samples. PGRN overexpression conferred GBM cells with tumorigenic properties and TMZ resistance by upregulating DNA repair (PARP, ATM, BRCA1, Rad51, XRCC1 and so on) and cancer stemness (CD133, CD44, ABCG2) genes, in part via an AP-1 transcription factor, specifically cFos/JunB. Curcumin, an AP-1 inhibitor, was also found to regulate PGRN promoter activity and expression including its downstream effectors aforementioned. These data suggested a feedforward loop between PGRN signaling and AP-1. PGRN depletion significantly decreased unlimited self-renewal and multilineage differentiation and the malignant properties of GBMs cells S1R1, and enhanced their vulnerability to TMZ. In addition, S1R1 depleted of PGRN also lost the ability to form tumor in an orthotopic xenograft mouse model. In conclusion, PGRN had a critical role in the pathogenesis and chemoresistance of GBM and functioned at the top of the hierarchy of cellular machinery that modulates both DNA repair pathways and cancer stemness. Our data suggest that a new strategy combining current regimens with compounds targeting PGRN/AP-1 loop like curcumin may significantly improve the therapeutic outcome of GBM.
机译：多形性胶质母细胞瘤 （GBM） 是预后不佳的成人中最常见的恶性脑肿瘤。目前手术切除联合替莫唑胺 （TMZ） 和放疗的疗法仅略微延长了 GBM 患者的生存期。因此，必须阐明其高度恶性特性背后的机制，以便制定有效的治疗方案。在这项研究中，我们发现颗粒蛋白原 （PGRN） 在大多数 GBM 细胞系和大多数人类肿瘤样本中过表达。PGRN 过表达通过上调 DNA 修复（PARP、ATM、BRCA1、Rad51、XRCC1 等）和癌症干性（CD133、CD44、ABCG2）基因（部分通过 AP-1 转录因子，特别是 cFos/JunB）赋予 GBM 细胞致瘤特性和 TMZ 抗性。姜黄素是一种 AP-1 抑制剂，也被发现可以调节 PGRN 启动子的活性和表达，包括其上述下游效应子。这些数据表明 PGRN 信号转导和 AP-1 之间存在前馈环路。PGRN耗竭显著降低了GBMs细胞S1R1的无限自我更新和多谱系分化以及恶性特性，并增强了其对TMZ的脆弱性。此外，在原位异种移植小鼠模型中，PGRN耗尽的S1R1也失去了形成肿瘤的能力。总之，PGRN在GBM的发病机制和化疗耐药性中起着关键作用，并在调节DNA修复途径和癌症干性的细胞机制层次结构中发挥作用。我们的数据表明，将当前方案与靶向 PGRN/AP-1 环的化合物（如姜黄素）相结合的新策略可能会显着改善 GBM 的治疗结果。

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  • 来源
    《Oncogene》 |2015年第14期|1853-1864|共12页
  • 作者

    Bandey I.; Chiou S-H; Huang A-PTsai J-CTu P-h;

  • 作者单位

    Natl Yang Ming Univ, Taiwan Int Grad Program Mol Med, Taipei 112, Taiwan;

    Taipei Vet Gen Hosp, Dept Ophthalmol, Taipei, Taiwan;

    Natl Taiwan Univ, Natl Taiwan Univ Hosp, Coll Med, Sect Neurosurg,Dept Surg, Taipei 10764, Taiwan;

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  • 原文格式 PDF
  • 正文语种 英语
  • 中图分类 肿瘤学;
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