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DDX3 loss by p53 inactivation promotes tumor malignancy via the MDM2/Slug/E-cadherin pathway and poor patient outcome in non-small-cell lung cancer

Oncogene volume 33, pages 1515–1526 (2014)Cite this article

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Abstract

P53 inactivation by p53 mutation and E6 oncoprotein has a crucial role in human carcinogenesis. DDX3 has been shown to be a target of p53. In this study, we hypothesized that DDX3 loss by p53 inactivation may promote tumor malignancy and poor patients’ outcome. Mechanically, DDX3 loss by p53 knockdown and E6 overexpression was observed in A549 lung cancer cells. Conversely, DDX3 expression was markedly elevated by wild-type (WT) p53 ectopic expression in p53-null H1299 cells, E6-knockdown TL-1 lung cancer and SiHa cervical cancer cells. Interestingly, DDX3 loss promotes soft-agar growth and invasive capability; however, both capabilities were suppressed by DDX3 overexpression. We next expected that DDX3 loss might result in Slug-suppressed E-cadherin expression via decreased MDM2-mediated Slug degradation. As expected, MDM2 transcription is suppressed by DDX3 loss via decreased SP1 binding activity to the MDM2 promoter. Consequently, Slug expression was elevated by the reduction of MDM2 because of DDX3 loss, and E-cadherin expression was suppressed by Slug. Consistent observations in the correlation of DDX3 loss with MDM2, Slug and E-cadherin were seen in lung tumors from lung cancer patients. In addition, patients with low-DDX3 tumors had poorer survival and relapse than patients with high-DDX3 tumors. In conclusion, we suggest that DDX3 loss by p53 inactivation via MDM2/Slug/E-cadherin pathway promotes tumor malignancy and poor patient outcome.

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Acknowledgements

This work was jointly supported by grants from the National Health Research Institute (NHRI96-TD-G-111-006; NHRI97-TD-G-111-006) and the National Science Council (NSC-96-2628-B-040-002-MY3; DOH100-TD-C-111-005) of Taiwan, ROC.

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Authors and Affiliations

  1. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC

    D-W Wu, Y-W Cheng & H Lee

  2. Department of Surgery, Divison of Thoracic Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, ROC

    M-C Lee

  3. Department of Pathology, Taichung Veterans General Hospital, Taichung, Taiwan, ROC

    J Wang

  4. Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC

    C-Y Chen

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  1. D-W Wu
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Correspondence to H Lee.

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Wu, DW., Lee, MC., Wang, J. et al. DDX3 loss by p53 inactivation promotes tumor malignancy via the MDM2/Slug/E-cadherin pathway and poor patient outcome in non-small-cell lung cancer. Oncogene 33, 1515–1526 (2014). https://doi.org/10.1038/onc.2013.107

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