NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKK beta/NF-kappa B activation

作者：Chen Po Ming; Wu Tzu Chin; Cheng Ya Wen; Chen Chih Yi; Lee Huei^*

来源：Oncotarget, 2015, 6(16): 14274-14289.

DOI：10.18632/oncotarget.3695

• NKX2-1
• p53
• IKK beta
• lung adenocarcinoma

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 IKK beta transcription in p53-mutant cells, but NKX2-1-mediated wild-type p53 down-regulates IKK beta transcription via decreased Sp1 binding to IKK beta promoter in p53-WT cells. The IKK beta-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-IKK beta 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 IKK beta mRNA in p53-WT subgroup, but positively related with IKK beta 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.

• 出版日期2015-6-10
• 单位中国医科大学