The Epstein-Barr virus-encoded microRNA MiR-BART9 promotes tumor metastasis by targeting E-cadherin in nasopharyngeal carcinoma.
The Epstein-Barr virus-encoded microRNA MiR-BART9 promotes tumor metastasis by targeting E-cadherin in nasopharyngeal carcinoma.
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DOI：
10.1371/journal.ppat.1003974
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Chen HC
中科院分区：
文献类型：
--
作者：
Hsu CY;Yi YH;Chang KP;Chang YS;Chen SJ;Chen HC
microRNA（miRNAs）是一类负调控蛋白质编码基因表达的小RNA分子家族，在调控多种细胞过程中发挥重要作用。病毒也利用这种调节机制来指导其生命周期并逃避宿主免疫系统。EB病毒（EBV）是一种致癌病毒，与多种人类疾病密切相关，包括鼻咽癌（NPC），这是一种高度转移性的肿瘤类型，在南亚经常报告。已经发现几种病毒蛋白促进NPC细胞的迁移和侵袭。然而，并非所有的肿瘤组织都表达这些病毒癌蛋白，这表明其他机制可能有助于NPC肿瘤细胞的侵袭行为。我们小组先前的测序研究显示，EBV miRNA miR-BART 9在所有EBV阳性NPC组织中均以高水平表达。在本研究中，我们使用功能获得和功能丧失方法来研究miR-BART 9在EBV阴性和EBV阳性NPC细胞中的作用。我们发现miR-BART 9促进培养的NPC细胞的迁移和侵袭。在体外观察到的促迁移活性表现为增强的体内转移能力。计算分析显示，miR-BART 9可能靶向E-钙粘蛋白，这是一种在保护细胞-细胞连接和上皮表型中起关键作用的膜蛋白。通过生物化学测定和功能拯救分析，我们证实miR-BART 9特异性抑制E-钙粘蛋白以诱导间充质样表型并促进NPC细胞的迁移。这些结果表明miR-BART 9是一种促转移性病毒miRNA，并表明EBV阳性NPC细胞中高水平的miR-BART 9可能有助于肿瘤细胞的侵袭性。microRNA（miRNAs）是一类负调控蛋白质编码基因表达并协调多种细胞过程的小RNA分子家族。病毒也利用这种调节机制来管理其生命周期并逃避宿主免疫系统。EB病毒（Epstein-Barr virus，EBV）与鼻咽癌（nasopharyngeal carcinoma，NPC）密切相关。我们小组先前的研究发现，EBV miRNA miR-BART 9在所有EBV阳性NPC组织中以高水平表达。在本研究中，我们使用功能获得和功能丧失方法来研究miR-BART 9在EBV阴性和EBV阳性NPC细胞中的功能。我们发现miR-BART 9促进了培养的NPC细胞的迁移和侵袭力，并增强了体内NPC肿瘤的转移能力。通过计算分析，我们发现E-cadherin是一种对维持细胞间接触和抑制肿瘤转移至关重要的膜蛋白，是miR-BART 9的潜在靶点。通过生物化学测定和功能拯救分析，我们证实了miR-BART 9特异性抑制E-钙粘蛋白以增强NPC细胞的运动性。我们的研究结果表明，miR-BART 9是一种促转移的病毒miRNA，并表明miR-BART 9可能有助于EBV阳性NPC肿瘤的侵袭性。
MicroRNAs (miRNAs) are a family of small RNA molecules that negatively regulate the expression of protein-coding genes and play critical roles in orchestrating diverse cellular processes. This regulatory mechanism is also exploited by viruses to direct their life cycle and evade the host immune system. Epstein-Barr virus (EBV) is an oncogenic virus that is closely associated with multiple human diseases, including nasopharyngeal carcinoma (NPC), which is a highly metastatic type of tumor and is frequently reported in South Asia. Several viral proteins have been found to promote the migration and invasiveness of NPC cells. However, not all tumor tissues express these viral oncoproteins, suggesting that other mechanisms may contribute to the aggressive behavior of NPC tumor cells. A previous sequencing study by our group revealed that the EBV miRNA miR-BART9 was expressed at high levels in all EBV-positive NPC tissues. In the present study, we used gain- and loss-of-function approaches to investigate the effect of miR-BART9 in EBV-negative and EBV-positive NPC cells. We discovered that miR-BART9 promotes the migration and invasiveness of cultured NPC cells. The promigratory activity observed in vitro was manifested as an enhanced metastatic ability in vivo. Computational analysis revealed that miR-BART9 may target E-cadherin, a membrane protein that is pivotal in preserving cell-cell junctions and the epithelial phenotype. Through biochemical assays and functional rescue analysis, we confirmed that miR-BART9 specifically inhibits E-cadherin to induce a mesenchymal-like phenotype and promote the migration of NPC cells. These results indicated that miR-BART9 is a prometastatic viral miRNA and suggested that high levels of miR-BART9 in EBV-positive NPC cells may contribute to the aggressiveness of tumor cells. MicroRNAs (miRNAs) are a family of small RNA molecules that negatively regulate the expression of protein-coding genes and orchestrate diverse cellular processes. This regulatory mechanism is also exploited by viruses to manage their life cycle and to evade the host immune system. Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC), which is a highly metastatic type of tumor. A previous by our group study discovered that the EBV miRNA miR-BART9 is expressed at high levels in all EBV-positive NPC tissues. In the present study, we used gain- and loss-of-function approaches to investigate the function of miR-BART9 in EBV-negative and EBV-positive NPC cells. We showed that miR-BART9 promotes the migration and invasiveness of cultured NPC cells and enhances the metastatic ability of NPC tumors in vivo. Through computational analysis, we discovered that E-cadherin, a membrane protein that is critical for maintaining cell-cell contact and suppressing tumor metastasis, is a potential target for miR-BART9. Through biochemical assays and a functional rescue analysis, we confirmed that miR-BART9 specifically inhibits E-cadherin to enhance the motility of NPC cells. Our results show that miR-BART9 is a prometastatic viral miRNA and suggest that miR-BART9 may contribute to the aggressiveness of EBV-positive NPC tumors.
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影响因子：
6.7
作者：
Kong QL;Hu LJ;Cao JY;Huang YJ;Xu LH;Liang Y;Xiong D;Guan S;Guo BH;Mai HQ;Chen QY;Zhang X;Li MZ;Shao JY;Qian CN;Xia YF;Song LB;Zeng YX;Zeng MS
通讯作者：
Zeng MS
影响因子：
11.2
作者：
Ahmad A;Aboukameel A;Kong D;Wang Z;Sethi S;Chen W;Sarkar FH;Raz A
通讯作者：
Raz A
影响因子：
5.4
作者：
Allen, MD;Young, LS;Dawson, CW
通讯作者：
Dawson, CW
影响因子：
3.4
作者：
Bar-Sela, G;Kuten, A;Ben-Izhak, O
通讯作者：
Ben-Izhak, O
爱泼斯坦 - 巴尔病毒编码的microRNA mir-bart2下调病毒DNA聚合酶BALF5。
影响因子：
14.9
作者：
Barth, Stephanie;Pfuhl, Thorsten;Mamiani, Alfredo;Ehses, Claudia;Roemer, Klaus;Kremmer, Elisabeth;Jaeker, Christoph;Hoeck, Julia;Meister, Gunter;Graesser, Friedrich A.
通讯作者：
Graesser, Friedrich A.