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

D. W. Wu, M. C. Lee, J. Wang, C. Y. Chen, Y. W. Cheng, H. Lee

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1515-1526
Number of pages12
JournalOncogene
Volume33
Issue number12
DOIs
Publication statusPublished - Mar 20 2014

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Gastropoda
Cadherins
Non-Small Cell Lung Carcinoma
Neoplasms
Lung Neoplasms
Null Lymphocytes
Oncogene Proteins
Uterine Cervical Neoplasms
Agar
Carcinogenesis
Recurrence
Lung
Mutation
Survival
Growth

Keywords

  • DDX3
  • Lung cancer
  • P53 inactivation
  • Relapse
  • Survival

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

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. / Wu, D. W.; Lee, M. C.; Wang, J.; Chen, C. Y.; Cheng, Y. W.; Lee, H.

In: Oncogene, Vol. 33, No. 12, 20.03.2014, p. 1515-1526.

Research output: Contribution to journalArticle

Wu, D. W. ; Lee, M. C. ; Wang, J. ; Chen, C. Y. ; Cheng, Y. W. ; Lee, H. / 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. In: Oncogene. 2014 ; Vol. 33, No. 12. pp. 1515-1526.
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