NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKβ/NF-κB activation

Po Ming Chen, Tzu Chin Wu, Ya Wen Cheng, Chih Yi Chen, Huei Lee

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Abstract

NKX2-1 plays a dual role in lung adenocarcinoma progression, but the underling mechanism is not fully understood. In the present study, we provide evidence that NKX2-1 directly regulates p53 transcription, and in turn, NKX2-1 elevates the mutant p53/NF-Y complex to up-regulate IKKβ transcription in p53-mutant cells, but NKX2-1-mediated wild-type p53 down-regulates IKKβ transcription via decreased Sp1 binding to IKKβ promoter in p53-WT cells. The IKKβ-mediated p65 nuclear localization and epithelial-to-mesenchymal transition (EMT) modulated by the NKX2-1/p53 axis is responsible for soft-agar growth, invasion, and xenograft tumour formation. Among patients, high-IKKβ mRNA tumours had higher prevalence in p53-mutant or nuclear p65 tumours than their counterparts, but not related with NKX2-1 mRNA expression. However, when tumours were divided into p53-WT and p53-mutant subgroups, NKX2-1 mRNA expression was negatively correlated with IKKβ mRNA in p53-WT subgroup, but positively related with IKKβ mRNA expression in p53-mutant subgroup. Kaplan-Meier and Cox regression analysis indicated that high NKX2-1 mRNA tumours exhibited poorer overall survival and relapse free survival than low NKX2-1 mRNA tumours in p53-WT subgroup, but the opposite was observed in p53-mutant subgroup. Therefore, we suggest that NKX2-1 as a tumour suppressor or a tumour promoter in lung adenocarcinoma progression is dependent on p53 status.

Original languageEnglish
Pages (from-to)14274-14289
Number of pages16
JournalOncotarget
Volume6
Issue number16
Publication statusPublished - 2015

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Keywords

  • IKKβ
  • Lung adenocarcinoma
  • NKX2-1
  • p53

ASJC Scopus subject areas

  • Oncology

Cite this

Chen, P. M., Wu, T. C., Cheng, Y. W., Chen, C. Y., & Lee, H. (2015). NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKβ/NF-κB activation. Oncotarget, 6(16), 14274-14289.