Abstract 778: Suppression of lung adenocarcinoma progression by NKX2-1 is dependent on p53 Status.

This article investigates the mechanistic aspects of NKX2-1 as a tumour suppressor and its oncogenic properties in lung adenocarcinoma. We show that NKX2-1 is a transcriptional factor that directly regulates p53 transcription. In p53 wild-type cells, NKX2-1 interacts with SP1 to down-regulate IKKβ transcription. In p53 mutated cells, NKX2-1 elevates the mutant p53/NF-Y complex to up-regulate IKKβ transcription. NKX2-1-mediated IKKβ expression is responsible for the efficacy of soft agar growth, invasion, and xenograft lung tumour nodule formation. Moreover, tumour aggressiveness attenuated by NKX2-1-mediated IKKβ is predominately through the shuffling of Foxo3a between the cytosol and nucleus of lung cancer cells to modulate E-cadherin expression. A consistent association of NKX2-1 with IKKβ and E-cadherin expression was observed in tumours from lung adenocarcinoma patients. P53 mutated tumours with high NKX2-1 expression have poorer overall survival (OS) and relapse-free survival (RFS) rates than those with low-NKX2-1 expression. Conversely, p53 wild-type tumours with high-NKX2-1 tumours have more favourable OS and RFS rates than those with low-NKX2-1 expression. As such, we demonstrate that aberrant transcription of IKKβ underlines the ability of NKX2-1 to act as a tumour suppressor or to display oncogenic properties in lung adenocarcinoma. Citation Format: Huei Lee, Po-Ming Chen, Tzu-Chin Wu, Yawen Cheng, Chih-Yi Chen. Suppression of lung adenocarcinoma progression by NKX2-1 is dependent on p53 Status. [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 778. doi:10.1158/1538-7445.AM2013-778