Schmitt D C, Madeira da Silva L, Zhang W, Liu Z, Arora R, Lim S, Schuler A M, McClellan S, Andrews J F, Kahn A G, Zhou M, Ahn E-Y E, Tan M
Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
1] Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA [2] Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha 410013, China [3] Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha 410078, China.
Cell Death Dis. 2015 May 7;6(5):e1742. doi: 10.1038/cddis.2015.116.
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.
尽管表皮生长因子受体2（ErbB2/HER2）癌基因在癌症中的作用已得到广泛研究，但ErbB2如何被调控仍知之甚少。最近在ErbB2基因的一个内含子中发现了一种新型微小RNA，即mir-4728。然而，这种内含子微小RNA的功能和临床相关性完全未知。在此，我们证明mir-4728是丝裂原活化蛋白激酶（MAPK）信号传导的负调节因子，它通过直接靶向细胞外信号调节激酶（ERK）上游激酶MST4发挥作用，并在体外和动物模型中展现出多种肿瘤抑制特性。重要的是，我们对患者样本的研究表明，与正常组织相比，mir-4728在乳腺肿瘤中表达下调，且mir-4728的缺失与患者总体生存率较差相关。这些结果强烈表明，mir-4728是一种通过靶向MST4来控制MAPK信号传导的肿瘤抑制性微小RNA，揭示了mir-4728作为癌症潜在预后因素和治疗干预靶点的重要性。此外，本研究通过提供有力证据表明肿瘤抑制性微小RNA可拮抗其宿主癌基因的经典信号传导，代表了一个概念上的进展。
