Stem Cell Reviews and Reports ( IF 4.5 ) Pub Date : 2021-01-09 , DOI: 10.1007/s12015-020-10112-8 Jia Feng 1 , Qi Chen 1 , Ping Zhang 1 , Xiaodong Huang 2 , Weiguo Xie 2 , Hongyu Zhang 1 , Paul Yao 1
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Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with poor prognosis. In this study, we aimed to investigate the potential mechanism of latent membrane protein 1 (LMP1)-mediated tumorigenesis and provide a novel therapeutic strategy for targeting the EBV DNA genome. We found that LMP1 upregulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1β (PGC1β) through activation of nuclear factor-κB (NF-κB). Furthermore, the activated PGC1β upregulated the expression of 8-oxoguanine DNA glycosylase (OGG1) through the coactivation of nuclear respiratory factor 1 (NRF1) and GA-binding protein α (GABPα), preventing reactive oxygen species (ROS)-mediated base incision in the EBV genome and favoring its survival. Interruption of hexokinase domain component 1 (HKDC1) by either shRNA or Tf-D-HKC8 peptide suppressed the interaction of HKDC1 with voltage-dependent anion channel 1 (VDAC1), triggering mitochondrial dysfunction and excessive generation of ROS, thus resulting in EBV suppression through ROS-mediated DNA damage. Suppression of the EBV genome inhibited the expression of the LMP1/PGC1β/HKDC1/OGG1 signaling pathway, forming a positive feed forward loop for the generation of ROS, hence inhibiting the EBV genome and subsequent EBV-associated tumor development. We concluded that LMP1 triggers EBV-associated tumorigenesis through activation of the PGC1β pathway. This study provided a novel therapeutic strategy for the treatment of EBV-associated tumors by targeting HKDC1.
Graphical Abstract
中文翻译：
潜在膜蛋白 1 通过上调 PGC1β 信号通路促进肿瘤发生
自然杀伤/T细胞淋巴瘤（NKTCL）是一种侵袭性爱泼斯坦-巴尔病毒（EBV）相关的非霍奇金淋巴瘤，预后较差。在这项研究中，我们旨在研究潜在的膜蛋白 1 (LMP1) 介导的肿瘤发生的潜在机制，并为靶向 EBV DNA 基因组提供一种新的治疗策略。我们发现 LMP1 通过激活核因子-κB (NF-κB) 上调过氧化物酶体增殖物激活受体-γ (PPARγ) coactivator-1β (PGC1β) 的表达。此外，活化的 PGC1β 通过核呼吸因子 1 (NRF1) 和 GA 结合蛋白 α (GABPα) 的共激活上调 8-氧鸟嘌呤 DNA 糖基化酶 (OGG1) 的表达，防止活性氧 (ROS) 介导的碱基切口EBV 基因组并有利于其生存。shRNA 或 Tf-D-HKC8 肽对己糖激酶结构域组分 1 (HKDC1) 的中断抑制了 HKDC1 与电压依赖性阴离子通道 1 (VDAC1) 的相互作用，从而引发线粒体功能障碍和 ROS 的过度产生，从而导致通过抑制 EBV ROS介导的DNA损伤。EBV基因组的抑制抑制了LMP1/PGC1β/HKDC1/OGG1信号通路的表达，形成了产生ROS的正前馈环，从而抑制了EBV基因组和随后的EBV相关肿瘤的发展。我们得出结论，LMP1 通过激活 PGC1β 途径触发 EBV 相关的肿瘤发生。本研究通过靶向 HKDC1 为治疗 EBV 相关肿瘤提供了一种新的治疗策略。
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