miR-141 is involved in BRD7-mediated cell proliferation and tumor formation through suppression of the PTEN/AKT pathway in nasopharyngeal carcinoma
miR-141 is involved in BRD7-mediated cell proliferation and tumor formation through suppression of the PTEN/AKT pathway in nasopharyngeal carcinoma
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miR-141通过抑制鼻咽癌中的PTEN/AKT通路参与BRD7介导的细胞增殖和肿瘤形成
DOI：
10.1038/cddis.2016.64
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发表时间：
2016-03-01
影响因子：
9
通讯作者：
Zhou, M.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Zhao, R.;Zhou, M.
含溴域7 （Bromodomain containing 7, BRD7）是一种核转录调控因子。BRD7在包括鼻咽癌（NPC）在内的多种癌症中作为肿瘤抑制因子发挥作用。在这项研究中，我们报道了BRD7在鼻咽癌进展中的新机制。我们证明miR-141在鼻咽癌组织中的表达显著升高，并且与BRD7的表达和鼻咽癌患者的生存率呈负相关。与对照细胞相比，brd7过表达的HEK293、5-8F和HNE1细胞中miR-141的原代、前体和成熟形式的表达水平均有所降低，而对两种关键酶Drosha和Dicer的表达水平无明显影响。BRD7可以负向调节miR-141的启动子活性，而在miR-141的潜在启动子区域未发现BRD7的明显结合位点。此外，miR-141的异位表达可以显著促进鼻咽癌细胞增殖和抑制细胞凋亡，在体外和体内实验中，挽救过表达BRD7的鼻咽癌细胞中miR-141的表达可以部分逆转BRD7对细胞增殖和肿瘤生长的抑制作用。此外，通过挽救miR-141的表达，可以抑制BRD7过表达介导的PTEN/AKT通路的激活，从而导致细胞增殖和肿瘤生长的部分恢复。我们的研究结果表明，BRD7/miR-141/PTEN/AKT轴在鼻咽癌的进展中起关键作用，并为鼻咽癌的诊断和治疗提供了一些有希望的靶点。
Bromodomain containing 7 (BRD7) was identified as a nuclear transcriptional regulatory factor. BRD7 functions as a tumor suppressor in multiple cancers, including nasopharyngeal carcinoma (NPC). In this study, we reported a novel mechanism of BRD7 in NPC progression. We demonstrated that the expression of miR-141 was remarkably increased in NPC tissues and was negatively correlated with the expression of BRD7 and the survival rate of NPC patients. Decreased expression levels of miR-141, including the primary, the precursor and the mature forms of miR-141, were found in BRD7-overexpressing HEK293, 5-8F and HNE1 cells compared the control cells, while there was no obvious effect on the expression levels of the two critical enzymes Drosha and Dicer. BRD7 can negatively regulate the promoter activity of miR-141, while no obvious binding site of BRD7 was found in the potential promoter region of miR-141. Moreover, ectopic expression of miR-141 can significantly promote cell proliferation and inhibit apoptosis in NPC, and rescuing the expression of miR-141 in BRD7-overexpressing NPC cells could partially reverse the tumor suppressive effect of BRD7 on cell proliferation and tumor growth in vitro and in vivo. Furthermore, the activation of the PTEN/AKT pathway mediated by the overexpression of BRD7 could be inhibited by rescuing the expression of miR-141, which accordingly results in the partial restoration of cell proliferation and tumor growth. Our findings demonstrate that the BRD7/miR-141/PTEN/AKT axis has critical roles in the progression of NPC and provide some promising targets for the diagnosis and treatment of NPC.