野生型 IDH2 有助于 Epstein-Barr 病毒依赖性代谢改变和肿瘤发生。
Wild-type IDH2 contributes to Epstein-Barr virus-dependent metabolic alterations and tumorigenesis.
机构信息
Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha 410078, China; Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, China.
Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha 410078, China; Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, China; Molecular Imaging Research Center of Central South University, Changsha 410008, Hunan, China.
出版信息
Mol Metab. 2020 Jun;36:100966. doi: 10.1016/j.molmet.2020.02.009. Epub 2020 Feb 18.
OBJECTIVE
Epstein-Barr virus (EBV) is a well-recognized oncogenic virus that can induce host cell metabolic reprogramming and tumorigenesis by targeting vital metabolic enzymes or regulators. This study aims to explore the role of wild-type isocitrate dehydrogenase 2 (IDH2) in metabolic reprogramming and tumorigenesis induced by EBV-encoded latent membrane protein 1 (LMP1).
METHODS
Mechanistic dissection of wild-type IDH2 in EBV-LMP1-induced tumorigenesis was investigated using western blotting, real-time polymerase chain reaction (PCR), immunochemistry, chromatin immunoprecipitation (ChIP), and luciferase assay. The role of wild-type IDH2 was examined by cell viability assays/Sytox Green staining in vitro and xenograft assays in vivo.
RESULTS
IDH2 over-expression is a prognostic indicator of poorer disease-free survival for patients with head and neck squamous cell carcinoma (HNSCC). IDH2 expression is also upregulated in nasopharyngeal carcinoma (NPC, a subtype of HNSCC) tissues, which is positively correlated with EBV-LMP1 expression. EBV-LMP1 contributes to NPC cell viability and xenograft tumor growth mediated through wild-type IDH2. IDH2-dependent changes in intracellular α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG) contribute to EBV-LMP1-induced tumorigenesis in vitro and in vivo. Elevated serum 2-HG level is associated with high EBV DNA and viral capsid antigen-immunoglobulin A (VCA-IgA) levels in patients with NPC. A significantly positive correlation exists between serum 2-HG level and regional lymph node metastases of NPC. EBV-LMP1 enhances the binding of c-Myc with the IDH2 promoter and transcriptionally activates wild-type IDH2 through c-Myc. Targeting IDH2 decreased intracellular 2-HG levels and survival of EBV-LMP1-positive tumor cells in vitro and in vivo.
CONCLUSIONS
Our results demonstrate that the EBV-LMP1/c-Myc/IDH2 signaling axis is critical for EBV-dependent metabolic changes and tumorigenesis, which may provide new insights into EBV-related cancer diagnosis and therapy.
目的
EB 病毒（EBV）是一种公认的致癌病毒，可通过靶向重要代谢酶或调节剂来诱导宿主细胞代谢重编程和肿瘤发生。本研究旨在探讨野生型异柠檬酸脱氢酶 2（IDH2）在 EBV 编码的潜伏膜蛋白 1（LMP1）诱导的代谢重编程和肿瘤发生中的作用。
方法
使用 Western blot、实时聚合酶链反应（PCR）、免疫化学、染色质免疫沉淀（ChIP）和荧光素酶测定法研究 EBV-LMP1 诱导的肿瘤发生中野生型 IDH2 的机制。通过细胞活力测定/Sytox 绿染色在体外和异种移植实验中检测野生型 IDH2 的作用。
结果
IDH2 过表达是头颈部鳞状细胞癌（HNSCC）患者无病生存率较差的预后指标。鼻咽癌细胞（NPC，HNSCC 的一种亚型）组织中 IDH2 的表达也上调，并且与 EBV-LMP1 的表达呈正相关。EBV-LMP1 通过野生型 IDH2 促进 NPC 细胞活力和异种移植肿瘤生长。IDH2 依赖性细胞内α-酮戊二酸（α-KG）和 2-羟基戊二酸（2-HG）变化导致 EBV-LMP1 在体外和体内诱导的肿瘤发生。NPC 患者血清 2-HG 水平升高与 EBV DNA 和病毒衣壳抗原免疫球蛋白 A（VCA-IgA）水平升高相关。NPC 患者血清 2-HG 水平与局部淋巴结转移之间存在显著正相关。EBV-LMP1 通过 c-Myc 增强 c-Myc 与 IDH2 启动子的结合，并通过 c-Myc 转录激活野生型 IDH2。靶向 IDH2 降低了体内 2-HG 水平和 EBV-LMP1 阳性肿瘤细胞的存活率。
结论
我们的结果表明，EBV-LMP1/c-Myc/IDH2 信号轴对于 EBV 依赖性代谢变化和肿瘤发生至关重要，这可能为 EBV 相关癌症的诊断和治疗提供新的见解。
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