TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness.
TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness.
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DOI：
10.1186/1476-4598-13-51
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发表时间：
2014-03-08
期刊：
影响因子：
37.3
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Lyu X;Fang W;Cai L;Zheng H;Ye Y;Zhang L;Li J;Peng H;Cho WC;Wang E;Marincola FM;Yao K;Cai H;Li J;Li X
miR-17-92簇及其旁系同源物已经成为许多癌基因和肿瘤抑制因子的关键调节因子。转化生长因子-β受体Ⅱ（TGFβR2）是一种重要的肿瘤抑制因子，参与多种肿瘤的发生。然而，在癌症中，迄今为止仅报道了该簇的两种miRNA及其旁系同源物调节TGFβR2。miR-93是致癌的，但其在癌症中的靶向组尚未完全确定。miR-93在鼻咽癌（NPC）中的作用仍然很大程度上未知。我们首先评估了临床样本中TGFβR2下调的临床特征，然后使用miRNA表达谱分析，随后进行多重验证，包括荧光素酶报告基因分析，以鉴定NPC中靶向TGFβR2的miRNA。通过体外和体内研究进一步探讨miRNA介导的TGFβR2下调对NPC侵袭性的影响。最后，对miRNA介导的TGFβR2下调的相关通路和基因进行了研究。50%以上的鼻咽癌患者TGFβR2表达下调。它是一个不利的预后因素，有助于临床鼻咽癌的侵袭性。发现了4个TGFβR2相关的miRNAs簇，它们均来自miR-17-92簇及其旁系同源物，其中miR-93是最重要的miRNAs之一，直接靶向TGFβR2，在体外和体内促进细胞增殖、侵袭和转移。此外，miR-93通过抑制TGFβR2，减弱Smad依赖的TGF-β信号通路，激活PI 3 K/Akt通路，进一步促进NPC细胞的生长、侵袭、转移和EMT样过程。令人印象深刻的是，通过siRNA敲低TGFβR2在NPC细胞中显示出与miR-93的作用一致的表型，支持TGFβR2是miR-93的主要靶点。我们的研究结果也通过调查miR-93和TGFβR2在NPC中的临床特征得到了证实。本研究报告了miR-93介导的TGFβR2下调参与NPC侵袭性，从而对癌症侵袭性的分子机制提供了更深入的见解。旨在阻断miR-93的方法可以作为治疗NPC患者的有希望的治疗策略。
MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown. We firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation. TGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC. The present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.
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影响因子：
3.8
作者：
Borchert GM;Holton NW;Larson ED
通讯作者：
Larson ED
影响因子：
9
作者：
通讯作者：
--
影响因子：
8
作者：
Kim, K.;Chadalapaka, G.;Lee, S-O;Yamada, D.;Sastre-Garau, X.;Defossez, P-A;Park, Y-Y;Lee, J-S;Safe, S.
通讯作者：
Safe, S.
影响因子：
4.3
作者：
Fang, Ling;Du, William W.;Yang, Burton B.
通讯作者：
Yang, Burton B.
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影响因子：
4
作者：
Deng, Min;Tang, Hailin;Li, Guiyuan
通讯作者：
Li, Guiyuan