BRD7 expression and c-Myc activation forms a double-negative feedback loop that controls the cell proliferation and tumor growth of nasopharyngeal carcinoma by targeting oncogenic miR-141
BRD7 expression and c-Myc activation forms a double-negative feedback loop that controls the cell proliferation and tumor growth of nasopharyngeal carcinoma by targeting oncogenic miR-141
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BRD7表达和c-Myc激活形成双负反馈环，通过靶向致癌miR-141控制鼻咽癌的细胞增殖和肿瘤生长
DOI：
10.1186/s13046-018-0734-2
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发表时间：
2018-03-20
影响因子：
11.3
通讯作者：
Zhou, Ming
中科院分区：
文献类型：
--
作者：
Liu, Yukun;Zhao, Ran;Zhou, Ming
研究背景miR-141在鼻咽癌（nasopharyngeal carcinoma，NPC）中表达上调，并发挥重要作用。然而，miR-141调控异常的分子机制尚不清楚。采用qRT-PCR、western blot和免疫组织化学方法检测miR-141及其上下游分子的表达。结果c-Myc基因敲除鼻咽癌细胞中，成熟miR-141、pre-miR-141和pri-miR-141的表达水平下调。同时，c-Myc通过结合miR-141的启动子区反式激活miR-141的表达。此外，BRD 7被鉴定为c-Myc的辅因子以负调节c-Myc/miR-141轴的激活，以及c-Myc的直接靶点。此外，在c-Myc敲低的NPC细胞中恢复miR-141显著地挽救了c-Myc对细胞增殖和肿瘤生长的作用，以及对PTEN/AKT通路的阻断。此外，c-Myc的表达与miR-141的表达和NPC患者的临床分期呈正相关，与BRD 7的表达呈负相关。结论miR-141在鼻咽癌细胞中的表达调控机制可能与miR-141在鼻咽癌细胞中的表达调控有关，miR-141在鼻咽癌细胞中的表达调控可能与c-Myc的激活有关。
BackgroundmiR-141 is up-regulated and plays crucial roles in nasopharyngeal carcinoma (NPC). However, the molecular mechanism underlying the dysregulation of miR-141 is still obscure.MethodsThus, the ChIP-PCR was performed to identify the c-Myc-binding sites in miR-141 and BRD7. qRT-PCR, western blot and immunohistochemistry assays were used to detect the expression of miR-141 and its up/down stream molecules. The rescue experiments on the c-Myc/miR-141 axis were performed in vitro and in vivo.ResultsOur results showed that the levels of mature miR-141, pre-miR-141 and pri-miR-141 were downregulated in c-Myc knockdown NPC cells. Meanwhile, c-Myc transactivates the expression of miR-141 by binding its promoter region. Moreover, BRD7 was identified as a co-factor of c-Myc to negatively regulate the activation of c-Myc/miR-141 axis, as well as a direct target of c-Myc. Moreover, restoration of miR-141 in c-Myc knockdown NPC cells notably rescued the effect of c-Myc on cell proliferation and tumor growth, as well as the blocking of PTEN/AKT pathway. Additionally, the expression of c-Myc was positively correlated with that of miR-141 and the clinical stages of NPC patients and negatively associated with the expression of BRD7. Our findings demonstrated that BRD7 expression and c-Myc activation forms a negative feedback loop to control the cell proliferation and tumor growth by targeting miR-141.ConclusionsThese observations provide new mechanistic insights into the dysregulation of miR-141 expression and a promising therapeutic option for NPC.