Abstract 3096: miR-93-directed down-regulation of Dab2 defines a novel oncogenic pathway in lung cancer.

Abstract

Abstract Introduction. The Disabled homolog 2 (DAB2) gene is located on human chromosome 5p13 and expresses a mitogen-responsive phosphoprotein. Previous studies have indicated that DAB2 is a tumor suppressor gene and is down-regulated in multiple cancer types, suggesting that repressed DAB2 expression plays an important role in oncogenesis. Loss of Dab2 protein expression has also been observed in lung cancer. The molecular and clinical consequences of loss of Dab2 expression in lung cancers, however, have not been fully evaluated, and the mechanisms of its dysregulation in cancers need to be defined. Aims and Methods. We aim to determine the role of DAB2 in lung tumorigenesis, and the role of microRNAs (miRNAs) in regulating Dab2 expression in lung cancer cells. Using in silico and in vitro approaches, we identified DAB2 as a direct target of miR-93. Using in vitro approaches, we investigated the function of Dab2 and miR-93 in regulating lung cancer cell growth. To investigate the clinical significance of DAB2 and miR-93 dysregulation in lung cancer patients, we examined the correlation of miR-93 and DAB2 tumor levels with lung cancer patient survival, and investigated the correlation between miR-93 and DAB2 expression in lung tumor specimens. Results and Conclusions. We show that Dab2 overexpression significantly arrests cell growth in lung cancer cells in vitro, and that low DAB2 mRNA levels in human lung tumor specimens are significantly correlated with poor patient survival. These results indicate that Dab2 is a potent tumor suppressor in lung cancer and that DAB2 levels may be an important factor in determining lung cancer progression and prognosis. We show that miR-93 directly targets the 3’UTR of DAB2 mRNA, and that miR-93 levels are negatively correlated with DAB2 mRNA levels in lung cancer specimens. We also show that high miR-93 levels are correlated with poor patient survival. Together these results support the clinical importance of the miR-93/Dab2 regulatory pathway in lung cancer. Overall, our study identifies a novel oncogenic pathway in lung cancer mediated by over-expression of miR-93 and subsequent down-regulation of its target DAB2. The significant correlations of both DAB2 and miR-93 expression with patient survival highlight the critical role of this pathway in lung tumorigenesis. Future studies are needed to investigate whether therapeutic tools targeting this pathway could be developed for lung cancer treatment, and whether this pathway provides a valuable prognostic biomarker for lung cancer patient survival. Citation Format: Liqin Du, Zhenze Zhao, Emily Young, Xiuye Ma, Ignacio Wistuba, Alexander Pertsemlidis. miR-93-directed down-regulation of Dab2 defines a novel oncogenic pathway in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3096. doi:10.1158/1538-7445.AM2013-3096