<br>EBV-miR-BART22 诱导的 miR-4721 靶向 GSK3β，通过 WNT/β-catenin 通路增强 NPC 的致瘤能力,Molecular Therapy - Nucleic Acids

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EBV-miR-BART22 诱导的 miR-4721 靶向 GSK3β，通过 WNT/β-catenin 通路增强 NPC 的致瘤能力
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2020-09-23 , DOI: 10.1016/j.omtn.2020.09.021
ZiBo Tang , WeiFeng Chen , Yan Xu , Xian Lin , Xiong Liu , YongHao Li , YiYi Liu , ZhiJian Luo , Zhen Liu , Weiyi Fang , Mengyang Zhao

鼻咽癌（NPC）在东亚和东南亚很普遍。在之前的一项研究中，Epstein-Barr 病毒（EBV）-miR-BART22 诱导肿瘤转移和干性，并显着参与 NPC 进展。在本研究中，我们观察到 miR-4721 被 EBV-miR-BART22 通过磷脂酰肌醇 3-激酶（PI3K）/AKT/c-JUN/Sp1 信号传导诱导以促进其转录。在随后的研究中，我们观察到 miR-4721 在体外和体内作为一种潜在的致癌因子促进 NPC 细胞周期进程和细胞增殖。机制分析表明，miR-4721 直接靶向 GSK3β 并降低其表达，从而增加 β-catenin 核内聚集并激活其下游细胞周期因子，包括 CCND1 和 c-MYC。在临床样本中，分别观察到 miR-4721 和 GSK3β 在 NPC 进展中上调和下调。miR-4721 表达升高与临床进展和不良预后呈正相关。我们的研究首先证明，miR-4721 作为癌基因是由 EBV-miR-BART22 通过调节 PI3K/AKT/c-JUN/Sp1 信号传导靶向 GSK3β 诱导的，从而激活 WNT/β-catenin 刺激的细胞周期信号并增强 NPC 的致瘤能力。miR-4721 可能是未来 NPC 治疗的潜在生物标志物或治疗靶点。

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miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia. In a previous study, Epstein-Barr virus (EBV)-miR-BART22 induces tumor metastasis and stemness and is significantly involved in NPC progression. In the present study, we observed that miR-4721 is induced by EBV-miR-BART22 through phosphatidylinositol 3-kinase (PI3K)/AKT/c-JUN/Sp1 signaling to promote its transcription. In a subsequent study, we observed that miR-4721 serves as a potential oncogenic factor promoting NPC cell cycle progression and cell proliferation in vitro and in vivo. Mechanism analysis indicated that miR-4721 directly targetes GSK3β and reduces its expression, which therefore elevates β-catenin intra-nuclear aggregation and activates its downstream cell cycle factors, including CCND1 and c-MYC. In clinical samples, miR-4721 and GSK3β are respectively observed to be upregulated and downregulated in NPC progression. Elevated expression of miR-4721 is positively associated with clinical progression and poor prognosis. Our study first demonstrated that miR-4721 as an oncogene is induced by EBV-miR-BART22 via modulating PI3K/AKT/c-JUN/Sp1 signaling to target GSK3β, which thus activates the WNT/β-catenin-stimulated cell cycle signal and enhances the tumorigenic capacity in NPC. miR-4721 may be a potential biomarker or therapeutic target in NPC treatment in the future.

更新日期：2020-09-23

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