Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
EMBO Mol Med. 2010 Jul;2(7):275-88. doi: 10.1002/emmm.201000081.
Apoptosis is a fundamental host defence mechanism against invading microbes. Inactivation of NF-kappaB attenuates encephalomyocarditis virus (EMCV) virulence by triggering rapid apoptosis of infected cells, thereby pre-emptively limiting viral replication. Recent evidence has shown that hypoxia-inducible factor (HIF) increases NF-kappaB-mediated anti-apoptotic response in clear-cell renal cell carcinoma (CCRCC) that commonly exhibit hyperactivation of HIF due to the loss of its principal negative regulator, von Hippel-Lindau (VHL) tumour suppressor protein. Here, we show that EMCV challenge induces a strong NF-kappaB-dependent gene expression profile concomitant with a lack of interferon-mediated anti-viral response in VHL-null CCRCC, and that multiple established CCRCC cell lines, as well as early-passage primary CCRCC cultured cells, are acutely susceptible to EMCV replication and virulence. Functional restoration of VHL or molecular suppression of HIF or NF-kappaB dramatically reverses CCRCC cellular susceptibility to EMCV-induced killing. Notably, intratumoural EMCV treatment of CCRCC in a murine xenograft model rapidly regresses tumour growth. These findings provide compelling pre-clinical evidence for the usage of EMCV in the treatment of CCRCC and potentially other tumours with elevated HIF/NF-kappaB-survival signature.
细胞凋亡是宿主抵抗入侵微生物的基本防御机制。NF-κB 的失活通过触发感染细胞的快速凋亡来减弱脑心肌炎病毒 (EMCV) 的毒力，从而预先限制病毒复制。最近的证据表明，缺氧诱导因子 (HIF) 增加了 NF-κB 介导的抗凋亡反应，在常因主要负调节剂 von Hippel-Lindau (VHL) 肿瘤抑制蛋白缺失而导致 HIF 过度激活的透明细胞肾细胞癌 (CCRCC) 中更是如此。在这里，我们表明 EMCV 挑战会诱导强烈的 NF-κB 依赖性基因表达谱，同时缺乏干扰素介导的抗病毒反应在 VHL 缺失的 CCRCC 中，并且多个已建立的 CCRCC 细胞系以及早期传代的原发性 CCRCC 培养细胞对 EMCV 复制和毒力非常敏感。VHL 的功能恢复或 HIF 或 NF-κB 的分子抑制可显著逆转 CCRCC 细胞对 EMCV 诱导杀伤的敏感性。值得注意的是，在 CCRCC 的小鼠异种移植模型中，肿瘤内 EMCV 治疗可迅速使肿瘤生长消退。这些发现为 EMCV 在 CCRCC 及其他可能具有升高的 HIF/NF-κB 存活特征的肿瘤的治疗中的应用提供了令人信服的临床前证据。
