Department of Pathogenic Biology, Qingdao University Medical College, Qingdao, China.
Department of Clinical Laboratory, Zibo Central Hospital, Zibo, China.
Microbiol Spectr. 2022 Jun 29;10(3):e0000622. doi: 10.1128/spectrum.00006-22. Epub 2022 Jun 8.
Epstein-Barr virus (EBV), a ubiquitous oncogenic herpesvirus, infects more than 90% of the adult population worldwide. The long noncoding RNA H19 is downregulated in EBV-positive gastric cancer (EBVaGC) and nasopharyngeal cancer (NPC). In this study, we found that loss of H19 is caused by hypermethylation status of the H19 promoter in EBV-positive GC and NPC cell lines. Furthermore, latent membrane protein 1 (LMP1), encoded by EBV, induced H19 promoter hypermethylation and deregulated the expression of H19 by upregulating DNMT1 expression. Transwell assays showed that H19 promoted cell migration. Furthermore, H19 promoted cell proliferation and inhibited apoptosis in CCK-8 and flow cytometry assays, respectively. p53, a well-known tumor suppressor, was upregulated in EBVaGC and NPC cell lines. miR-675-5p derived from H19 inhibited p53 protein expression by targeting the 3' untranslated region of the gene. Overall, we found that LMP1 induced p53 protein expression via the H19/miR-675-5p axis in EBVaGC and NPC. LMP1 induced H19 promoter hypermethylation, which repressed the expression of H19 and miR-675-5p and caused p53 protein overexpression in EBVaGC and NPC cells. Epstein-Barr virus (EBV) is the first virus to be known to have direct association with human cancer and to be considered as an important DNA tumor virus. The EBV life cycle consists of both latent and lytic modes of infection in B lymphocytes and epithelial cells. The persistence of EBV genomes in malignant cells promoted cell growth. p53, acting as a critical gatekeeper tumor suppressor, is involved in multiple virus-mediated tumorigeneses. Overexpression of p53 inhibits the ability of BZLF1 (EBV-encoded immediate early gene) to disrupt viral latency. In our study, we found LMP1 induces H19 promoter hypermethylation, which represses the expression of H19 and miR-675-5p and results in p53 protein overexpression in EBVaGC and NPC cells. These observations suggest a new mechanism of aberrant expression of p53 by LMP1, which facilitates EBV latency.
Epstein-Barr 病毒（EBV）是一种普遍存在的致癌疱疹病毒，感染了全球超过 90%的成年人。长链非编码 RNA H19 在 EBV 阳性胃癌（EBVaGC）和鼻咽癌（NPC）中下调。在这项研究中，我们发现 EBV 阳性 GC 和 NPC 细胞系中 H19 的缺失是由于 H19 启动子的 hypermethylation 状态引起的。此外，EBV 编码的潜伏膜蛋白 1（LMP1）诱导 H19 启动子 hypermethylation，并通过上调 DNMT1 表达来调节 H19 的表达。Transwell 分析表明，H19 促进细胞迁移。此外，H19 在 CCK-8 和流式细胞术分析中分别促进细胞增殖和抑制细胞凋亡。p53，一种众所周知的肿瘤抑制因子，在 EBVaGC 和 NPC 细胞系中上调。源自 H19 的 miR-675-5p 通过靶向基因的 3'UTR 抑制 p53 蛋白表达。总体而言，我们发现 LMP1 通过 H19/miR-675-5p 轴在 EBVaGC 和 NPC 中诱导 p53 蛋白表达。LMP1 诱导 H19 启动子 hypermethylation，抑制 H19 和 miR-675-5p 的表达，并导致 EBVaGC 和 NPC 细胞中 p53 蛋白过表达。Epstein-Barr 病毒（EBV）是第一个已知与人类癌症直接相关并被认为是重要的 DNA 肿瘤病毒。EBV 的生命周期包括 B 淋巴细胞和上皮细胞中的潜伏和裂解感染模式。恶性细胞中 EBV 基因组的持续存在促进了细胞生长。p53，作为一个关键的肿瘤抑制因子，参与了多种病毒介导的肿瘤发生。p53 的过度表达抑制了 BZLF1（EBV 编码的早期基因）破坏病毒潜伏期的能力。在我们的研究中，我们发现 LMP1 诱导 H19 启动子 hypermethylation，抑制 H19 和 miR-675-5p 的表达，并导致 EBVaGC 和 NPC 细胞中 p53 蛋白过表达。这些观察结果表明 LMP1 通过诱导 H19 启动子 hypermethylation，从而抑制 H19 和 miR-675-5p 的表达，导致 p53 蛋白过表达，从而导致 p53 蛋白的异常表达，这有助于 EBV 的潜伏。
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