NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKβ/NF-κB activation.
NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKβ/NF-κB activation.
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DOI：
10.18632/oncotarget.3695
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发表时间：
2015-06-10
期刊：
影响因子：
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通讯作者：
Lee H
中科院分区：
文献类型：
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作者：
Chen PM;Wu TC;Cheng YW;Chen CY;Lee H
NKX 2 -1在肺腺癌进展中起双重作用，但其潜在机制尚未完全了解。在本研究中，我们提供的证据表明，NKX 2 -1直接调节p53转录，反过来，NKX 2 -1提高突变型p53/NF-Y复合物，以上调p53突变细胞中IKKβ的转录，但NKX 2 -1介导的野生型p53通过减少Sp1与p53-WT细胞中IKKβ启动子的结合来下调IKKβ的转录。IKKβ介导的p65核定位和由NKX 2 -1/p53轴调节的上皮-间充质转化（EMT）负责软琼脂生长、侵袭和异种移植肿瘤形成。在患者中，高IKK β mRNA肿瘤在p53突变型或核p65肿瘤中的患病率高于其对应者，但与NKX 2 -1 mRNA表达无关。将肿瘤分为p53-WT和p53-突变两个亚组，p53-WT亚组中NKX 2 -1 mRNA表达与IKKβ mRNA表达呈负相关，p53-突变亚组中NKX 2 -1 mRNA表达与IKKβ mRNA表达呈正相关。Kaplan-Meier和考克斯回归分析显示，在p53-WT亚组中，高NKX 2 - 1 mRNA肿瘤的总生存期和无复发生存期低于低NKX 2 -1 mRNA肿瘤，而在p53-突变亚组中观察到相反的情况。因此，我们认为NKX 2 -1在肺腺癌进展中作为肿瘤抑制剂或肿瘤促进剂依赖于p53状态。
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.