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miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer

Oncogene volume 33, pages 4307–4315 (2014)Cite this article

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Abstract

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.

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Acknowledgements

We thank Vivienne Rebel and Nicholas Dybdal-Hargreaves for critical reading of the manuscript. This work was supported in part by R01 CA129632 (A Pertsemlidis) and Lung Cancer SPORE P50 CA70907 (JD Minna and II Wistuba) from the NCI, W81XWH-07-1-0306 from the Department of Defense (II Wistuba), Academic Excellence grant EDUD-7824-021007-US (A Pertsemlidis) from Sun Microsystems and Cancer Center Support grants P30 CA054174, P30 CA142543 and P30 CA016672.

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Authors and Affiliations

  1. Greehey Children’s Cancer Research Institute, UT Health Science Center at San Antonio, San Antonio, TX, USA

    L Du, Z Zhao, X Ma, T-H Hsiao, Y Chen, E Young & A Pertsemlidis

  2. Department of Cellular and Structural Biology, UT Health Science Center at San Antonio, San Antonio, TX, USA

    L Du & A Pertsemlidis

  3. Department of Epidemiology & Biostatistics, UT Health Science Center at San Antonio, San Antonio, TX, USA

    Y Chen

  4. Department of Thoracic/Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

    M Suraokar & I Wistuba

  5. Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA

    I Wistuba

  6. Hamon Center for Therapeutic Oncology Research and Departments of Pharmacology and Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, TX, USA

    J D Minna

  7. Department of Pediatrics, UT Health Science Center at San Antonio, San Antonio, TX, USA

    A Pertsemlidis

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  1. L Du
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Du, L., Zhao, Z., Ma, X. et al. miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer. Oncogene 33, 4307–4315 (2014). https://doi.org/10.1038/onc.2013.381

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