Du L, Zhao Z, Ma X, Hsiao T-H, Chen Y, Young E, Suraokar M, Wistuba I, Minna J D, Pertsemlidis A
1] Greehey Children's Cancer Research Institute, UT Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Cellular and Structural Biology, UT Health Science Center at San Antonio, San Antonio, TX, USA.
Greehey Children's Cancer Research Institute, UT Health Science Center at San Antonio, San Antonio, TX, USA.
Oncogene. 2014 Aug 21;33(34):4307-15. doi: 10.1038/onc.2013.381. Epub 2013 Sep 16.
The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types. The role of DAB2 in lung tumorigenesis, however, is not fully characterized, and the mechanisms of DAB2 dysregulation in lung cancer are not defined. Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function. We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3'UTR of the DAB2 mRNA. Using in vitro and in vivo approaches, we demonstrate that miR-93 overexpression has an important role in promoting lung cancer cell growth, and that its oncogenic function is primarily mediated by downregulating DAB2 expression. Our clinical investigations further indicate that high tumor levels of miR-93 are correlated with poor survival of lung cancer patients. The correlations of both low DAB2 and high miR-93 expression levels with poor patient survival strongly support the critical role of the miR-93/DAB2 pathway in determining lung cancer progression.
失能同源物2（DAB2）基因最近被鉴定为一种肿瘤抑制基因，其在多种癌症类型中的表达下调。然而，DAB2在肺癌发生中的作用尚未完全阐明，肺癌中DAB2失调的机制也不明确。在此，我们发现肺癌组织标本中DAB2水平较低与患者预后不良显著相关，并且DAB2过表达显著抑制培养的肺癌细胞的生长，表明其具有强大的肿瘤抑制功能。接下来，我们确定微小RNA miR-93通过直接靶向DAB2 mRNA的3'UTR发挥对DAB2表达的有效抑制作用。利用体外和体内实验方法，我们证明miR-93过表达在促进肺癌细胞生长中起重要作用，并且其致癌功能主要通过下调DAB2表达介导。我们的临床研究进一步表明，肺癌患者肿瘤中miR-93水平较高与患者预后不良相关。DAB2水平低和miR-93表达水平高均与患者预后不良相关，这有力地支持了miR-93/DAB2通路在决定肺癌进展中的关键作用。
