EBV-miR-BART8-3p 通过激活 NF-κB 和 Erk1/2 通路诱导鼻咽癌细胞上皮-间充质转化并促进其转移。
EBV-miR-BART8-3p induces epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma cells through activating NF-κB and Erk1/2 pathways.
机构信息
Fujian Medical University, Fuzhou, 350108, Fujian Province, China.
Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350011, Fujian Province, China.
出版信息
J Exp Clin Cancer Res. 2018 Nov 26;37(1):283. doi: 10.1186/s13046-018-0953-6.
BACKGROUND
Epstein-Barr virus (EBV) is ubiquitously associated with nasopharyngeal carcinoma (NPC). EBV encodes two groups of microRNAs (miRNAs) which are divided into BamHI fragment H rightward open reading frame 1 (BHRF1) and BamHI-A rightward transcripts (BART) microRNAs. EBV miR-BART has been found to be involved in the development and progression of NPC. However, so far the role of EBV-miR-BART8-3p in NPC progression remains unknown. This study aimed to investigate the role of EBV-miR-BART8-3p in NPC and explore the underlying mechanisms.
METHODS
miRNA expression was profiled in NPC and normal nasopharyngeal mucosal specimens using miRNA sequencing. EBV-miR-BART8-3p and RNF38 expression was quantified with qPCR assay. The migration, invasion and metastasis of NPC cells were evaluated using CCK-8, colony-forming, wound-healing, and migration and invasion assays. The expression levels of epithelial-mesenchymal transition (EMT)-related markers,metastasis-related markers and NF-κB and Erk1/2 signaling proteins were determined using Western blotting. Tumorigenic assay was performed to evaluate the pulmonary metastatic ability of NPC cells in vivo.
RESULTS
EBV BART miRNAs were highly over-expressed and co-expressed in NPC and might be associated with deactivated immune response in NPC according to the sequencing analysis. EBV-miR-BART8-3p expression was significantly higher in human NPC specimens than in normal nasopharyngeal mucosal specimens. EBV-miR-BART8-3p was found to promote NPC migration, invasion and metastasis, drove an EMT process and upregulated expression of metastasis-related proteins expression in NPC cells. Our data showed EBV-miR-BART8-3p directly targeted RNF38 in NPC cells.
CONCLUSION
The present study demonstrates that EBV-miR-BART8-3p plays a significant role in inducing EMT and promoting metastasis through directly targeting RNF38 in NPC cells via the activation of NF-κB and Erk1/2 signaling pathways. Our findings suggest that EBV-miR-BART8-3p is a potential therapeutic target for NPC.
背景
爱泼斯坦-巴尔病毒（EBV）与鼻咽癌（NPC）广泛相关。EBV 编码两组 microRNAs（miRNAs），分为 BamHI 片段 H 右向开放阅读框 1（BHRF1）和 BamHI-A 右向转录物（BART）miRNAs。已发现 EBV miR-BART 参与 NPC 的发生和发展。然而，到目前为止，EBV-miR-BART8-3p 在 NPC 进展中的作用仍不清楚。本研究旨在探讨 EBV-miR-BART8-3p 在 NPC 中的作用，并探讨其潜在机制。
方法
采用 miRNA 测序技术对 NPC 和正常鼻咽黏膜标本中的 miRNA 表达进行分析。采用 qPCR 法检测 EBV-miR-BART8-3p 和 RNF38 的表达。采用 CCK-8、集落形成、划痕愈合、迁移和侵袭实验评估 NPC 细胞的迁移、侵袭和转移能力。采用 Western blot 法检测上皮-间充质转化（EMT）相关标志物、转移相关标志物以及 NF-κB 和 Erk1/2 信号蛋白的表达水平。通过体内肿瘤发生实验评估 NPC 细胞的肺转移能力。
结果
EBV BART miRNAs 在 NPC 中高度过表达且共表达，根据测序分析，可能与 NPC 中失活的免疫反应有关。与正常鼻咽黏膜标本相比，人 NPC 标本中 EBV-miR-BART8-3p 的表达显著升高。EBV-miR-BART8-3p 促进 NPC 细胞迁移、侵袭和转移，驱动 EMT 过程，并上调 NPC 细胞中转移相关蛋白的表达。我们的数据显示，EBV-miR-BART8-3p 在 NPC 细胞中直接靶向 RNF38。
结论
本研究表明，EBV-miR-BART8-3p 通过 NF-κB 和 Erk1/2 信号通路的激活，直接靶向 NPC 细胞中的 RNF38，在诱导 EMT 和促进转移中发挥重要作用。我们的研究结果表明，EBV-miR-BART8-3p 是 NPC 的一个潜在治疗靶点。
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