Epstein-Barr Virus MicroRNA miR-BART5-3p Inhibits p53 Expression
Epstein-Barr Virus MicroRNA miR-BART5-3p Inhibits p53 Expression
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Epstein-Barr 病毒 miR-BART5-3p 抑制 p53 表达
DOI：
10.1128/jvi.01022-18
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发表时间：
2018-12-01
影响因子：
5.4
通讯作者：
Ma, Jian
中科院分区：
文献类型：
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作者：
Zheng, Xiang;Wang, Jia;Ma, Jian
EB病毒（Epstein-Barr virus，EBV）是第一个发现编码多种microRNA的人类病毒。它在病因学上与鼻咽癌和EBV相关的胃癌有关。在潜伏感染期间，只有少数EB病毒蛋白质表达，而EB病毒微小RNA（例如BamHI-A区域右侧转录物（BART）微小RNA）则高度表达。然而，这些BART miRNAs如何精确调控鼻咽癌和胃癌的肿瘤生长仍然不清楚。在这里，我们报告了EBV-miR-BART 5 - 3 p的上调促进鼻咽癌和胃癌细胞的生长。BART 5 - 3 p直接靶向肿瘤抑制基因TP 53的3 '-非翻译区（3'-UTR），从而下调CDKN 1A、BAX和FAS的表达，导致细胞周期进程加速和细胞凋亡抑制。BART 5 - 3 p参与了化疗药物的耐药性和电离辐射诱导的p53增加。此外，BART 5 - 3 p还促进p53蛋白的降解。BART 5 - 3 p是第一个被鉴定为抑制p53表达和功能的EBV-microRNA，这提示了EBV维持潜伏感染和促进EBV相关癌发展的一种新机制。重要信息EBV编码44种成熟microRNA，已被证明通过靶向宿主基因和自身病毒基因促进EBV相关疾病的发生。在EBV相关癌中，病毒蛋白的表达是有限的，但BART microRNA的表达是非常高的，这表明它们可能是EBV相关肿瘤发生的主要因素。p53是一种重要的肿瘤抑制因子。与大多数人类实体瘤不同，TP 53突变在鼻咽癌和EBV相关的胃癌组织中很少见，这表明某些EBV编码的产物可能抑制p53的功能。这项研究提供了第一个证据，证明BART microRNA可以通过直接靶向其3 '-UTR来抑制p53表达。这项研究表明，EBV可以使用其BART microRNA来调节p53的表达，从而维持其潜伏期并促进肿瘤发生。
Epstein-Barr virus (EBV) is the first human virus found to encode many microRNAs. It is etiologically linked to nasopharyngeal carcinoma and EBV-associated gastric carcinoma. During the latent infection period, there are only a few EBV proteins expressed, whereas EBV microRNAs, such as the BamHI-A region rightward transcript (BART) microRNAs, are highly expressed. However, how these BART miRNAs precisely regulate the tumor growth in nasopharyngeal carcinoma and gastric carcinoma remains obscure. Here, we report that upregulation of EBV-miR-BART5-3p promotes the growth of nasopharyngeal carcinoma and gastric carcinoma cells. BART5-3p directly targets the tumor suppressor gene TP53 on its 3'-untranslated region (3'-UTR) and consequently downregulates CDKN1A, BAX, and FAS expression, leading to acceleration of the cell cycle progress and inhibition of cell apoptosis. BART5-3p contributes to the resistance to chemotherapeutic drugs and ionizing irradiation-induced p53 increase. Moreover, BART5-3p also facilitates degradation of p53 proteins. BART5-3p is the first EBV-microRNA to be identified as inhibiting p53 expression and function, which suggests a novel mechanism underlying the strategies employed by EBV to maintain latent infection and promote the development of EBV-associated carcinomas.IMPORTANCE EBV encodes 44 mature microRNAs, which have been proven to promote EBV-associated diseases by targeting host genes and self-viral genes. In EBV-associated carcinomas, the expression of viral protein is limited but the expression of BART microRNAs is extremely high, suggesting that they could be major factors in the contribution of EBV-associated tumorigenesis. p53 is a critical tumor suppressor. Unlike in most human solid tumors, TP53 mutations are rare in nasopharyngeal carcinoma and EBV-associated gastric carcinoma tissues, suggesting a possibility that some EBV-encoded products suppress the functions of p53. This study provides the first evidence that a BART microRNA can suppress p53 expression by directly targeting its 3'-UTR. This study implies that EBV can use its BART microRNAs to modulate the expression of p53, thus maintaining its latency and contributing to tumorigenesis.