EBV-miR-BART7-3p Imposes Stemness in Nasopharyngeal Carcinoma Cells by Suppressing SMAD7
EBV-miR-BART7-3p Imposes Stemness in Nasopharyngeal Carcinoma Cells by Suppressing SMAD7
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EBV-miR-BART7-3p 通过抑制 SMAD7 赋予鼻咽癌细胞干性。
DOI：
10.3389/fgene.2019.00939
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发表时间：
2019-10-17
影响因子：
3.7
通讯作者：
Li, Xin
中科院分区：
文献类型：
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作者：
Cai, Longmei;Long, Yufei;Li, Xin
肿瘤干细胞样细胞具有“干细胞”特性，在各种癌症的进展、转移和耐药性中起着至关重要的作用。病毒microRNA（如EBV-miR-BART 7 - 3 p）作为外源性调控因子参与了鼻咽癌的恶性进展，提示病毒microRNA可能参与了鼻咽癌的干性形成。在本研究中，我们发现EBV-miR-BART 7 - 3 p诱导NPC细胞的干细胞性。我们首次报道了EBV-miR-BART 7 - 3 p在体外增加侧群细胞的百分比、肿瘤球的发育和干性标志物的表达水平。这种病毒microRNA还增强了体内NPC细胞的干细胞样或癌症起始特性。此外，我们发现SMAD 7是EBV-miR-BART 7 - 3 p的新靶基因，该靶基因抑制SMAD 7，激活TGF-β信号通路，最终增强NPC细胞的干细胞性。SMAD 7的沉默类似于NPC细胞中EBV-miR-BART 7 - 3 p产生的效应。在SMAD 7重建后，EBV-miR-BART 7 - 3 p表达细胞经历表型逆转。使用EBV阳性NPC细胞来进行实验验证。最后，我们进一步发现EBV-miR-BART 7 - 3 p在体外和体内增加了NPC的化疗抗性，支持EBV-miR-BART 7 -3导致NPC细胞的干细胞性增加并导致耐药性和癌症复发。总的来说，这项研究揭示了NPC细胞病毒microRNA相关的干细胞性的新机制。这种病毒microRNA及其相关的细胞基因可能是抑制鼻咽癌化疗耐药和复发的潜在治疗靶点。
Cancer stem-like cells, possessing "stemness" properties, play crucial roles in progression, metastasis, and drug resistance in various cancers. Viral microRNAs (such as EBV-miR-BART7-3p), as exogenous regulators, have been discovered to regulate malignant progression of nasopharyngeal carcinoma (NPC), suggesting a possible role of viral microRNAs in imposing stemness. In this study, we found that EBV-miR-BART7-3p induce stemness of NPC cells. We firstly reported that EBV-miR-BART7-3p increased the percentage of side population cells, the development of tumor spheres, and the expression level of stemness markers in vitro. This viral microRNA also enhanced stem-like or cancer-initiating properties of NPC cells in vivo. Besides, we identified SMAD7 as a novel target gene of EBV-miR-BART7-3p in addition to PTEN gene we previously reported; this viral microRNA suppressed SMAD7, led to activation of TGF-ss signaling, and eventually enhanced the stemness of NPC cells. Silencing of SMAD7 resembled the effects generated by EBV-miR-BART7-3p in NPC cells. After reconstitution of SMAD7, EBV-miR-BART7-3p-expressing cells underwent a phenotypic reversion. EBV-positive NPC cells were used to enable experimental validation. Finally, we further discovered that EBV-miR-BART7-3p increased chemo-resistance of NPC in vitro and in vivo, supporting that EBV-miR-BART7-3 resulted in increased stemness of NPC cells and lead to drug resistance and cancer recurrence. Overall, this study uncovered a novel mechanism underlying viral microRNA-associated stemness of NPC cells. This viral microRNA and its associated cellular genes may be potential therapeutic targets for restraining chemoresistance and recurrence of NPC.