ErbB2-intronic microRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling.
ErbB2-intronic microRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling.
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DOI：
10.1038/cddis.2015.116
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发表时间：
2015-05-07
影响因子：
9
通讯作者：
Tan M
中科院分区：
文献类型：
--
作者：
Schmitt DC;Madeira da Silva L;Zhang W;Liu Z;Arora R;Lim S;Schuler AM;McClellan S;Andrews JF;Kahn AG;Zhou M;Ahn EY;Tan M
虽然ErbB 2/HER 2癌基因在癌症中的作用已被广泛研究，但ErbB 2是如何调节的仍然知之甚少。最近在ErbB 2基因的内含子中发现了一种新的microRNA，mir-4728。然而，这种内含子miRNA的功能和临床意义是完全未知的。在这里，我们证明，mir-4728是一个负调节MAPK信号通过直接靶向ERK上游激酶MST 4，并在体外和动物模型中发挥许多肿瘤抑制特性。重要的是，我们的患者样本研究表明，与正常组织相比，mir-4728在乳腺肿瘤中表达不足，mir-4728的缺失与患者总体生存率下降相关。这些结果强烈表明，mir-4728是一种肿瘤抑制性miRNA，通过靶向MST 4控制MAPK信号传导，揭示了mir-4728作为癌症治疗干预的潜在预后因子和靶点的重要性。此外，这项研究通过提供强有力的证据表明肿瘤抑制性miRNA可以拮抗其宿主癌基因的经典信号传导，代表了概念上的进步。
Although the role of the ErbB2/HER2 oncogene in cancers has been extensively studied, how ErbB2 is regulated remains poorly understood. A novel microRNA, mir-4728, was recently found within an intron of the ErbB2 gene. However, the function and clinical relevance of this intronic miRNA are completely unknown. Here, we demonstrate that mir-4728 is a negative regulator of MAPK signaling through directly targeting the ERK upstream kinase MST4 and exerts numerous tumor-suppressive properties in vitro and in animal models. Importantly, our patient sample study shows that mir-4728 was under-expressed in breast tumors compared with normal tissue, and loss of mir-4728 correlated with worse overall patient survival. These results strongly suggest that mir-4728 is a tumor-suppressive miRNA that controls MAPK signaling through targeting MST4, revealing mir-4728's significance as a potential prognostic factor and target for therapeutic intervention in cancer. Moreover, this study represents a conceptual advance by providing strong evidence that a tumor-suppressive miRNA can antagonize the canonical signaling of its host oncogene.