NMI调控COX-2表达及其在肺癌生长中的作用机制和临床意义

The high expression of COX-2 is the hallmarker of lung tumorigenesis. It is of important significant to discover the novel and tumor-specific factors which regulate COX-2 expression. In our preliminary study, we pulled down and identified NMI as a new COX-2 promoter-binding protein in lung cancer cells by BSBP（biotin-strepatavidin-beads pulldown）and proteomics techniques. We also showed that NMI was highly expressed in lung cancer cells and tumor tissues, regulated COX-2 transcription and lung cancer cell growth. However, so far it is unclear about the molecular mechanisms by which the NMI regulates COX-2 expression and lung tumorigenesis as well as its clinical implications. In this study, we will knockdown or overexpress NMI in human lung cancer cell lines and animal models, and then study the effects of NMI on COX-2 expression, promoter activity, PGE2 production, and tumor tumor cell growth, thereby revealing the mechanisms of action of the NMI/COX-2 signaling pathway in lung tumorigenesis. Moreover,we will use tissue array, combining with the clinical data, to analyze the expression levels and the correlation of NMI/COX-2 in tumor tissues from lung cancer patients, and to evaluate their relationship with lung tumorigenesis, pathological staging and patient prognosis, thereby identifying the clinical implications of NMI/COX-2. The results from this study will provide theoretical and experimental basis for the identification of the NMI/COX-2 signaling as a new therapeutic target for lung cancer treatment.

环氧合酶COX-2高表达是肺癌发生发展的风向指标，发现新型的肿瘤特异性COX-2表达调控因子意义重大。前期研究中，我们利用BSBP垂钓技术和蛋白质组学方法，在肺癌细胞中垂钓和确定了一个新型的COX-2启动子DNA 结合蛋白NMI，并证实其在肺癌细胞和组织中高表达、可调控COX-2转录和肺癌细胞生长，但NMI如何调控COX-2继而影响肺癌发生发展的分子机制及其临床意义，目前尚不清楚。本项目拟在肺癌细胞和动物模型中敲低或过表达NMI，研究其对COX-2表达、启动子活性和PGE2产生的调控以及对肿瘤生长的影响，揭示NMI/COX-2信号通路在肺癌发生发展中的作用和分子机制；并利用组织芯片，结合临床资料，分析肺癌患者组织中NMI/COX-2的表达水平及两者表达的相关性，并评估其与肺癌发生、分期、复发、预后的关系，明确其临床意义。本项目将为确立NMI 作为肺癌治疗新靶点提供理论和实验依据。

环氧合酶（COX-2）高表达是肺癌进展的重要指标，对其调控机制的研究是关注的焦点。在本项目中，我们重点探讨了肺癌细胞中NMI对COX-2基因表达和功能活性的调控机制，研究了NMI在肺癌细胞中的生物学功能和作用机制，探索了NMI和COX-2表达的临床意义。重要结果和关键数据如下：①在肺癌细胞中NMI通过与p300相互作用抑制p300对转录因子p65乙酰化修饰，影响p65与COX-2启动子结合，进而抑制COX-2的转录活性、基因表达和抑制COX-2下游酶底物PGE2的分泌，NMI通过抑制COX-2的表达抑制细胞增殖和迁移。②在肺癌细胞中NMI还可以通过灭活PI3K/AKT通路和MAPK通路抑制肺癌细胞增殖和生长。③在肺癌细胞中NMI通过活化线粒体凋亡通路诱导细胞凋亡。④NMI通过下调MMP2和MMP9的表达抑制肺癌细胞迁移和EMT属性。⑤过表达NMI抑制异种移植小鼠肺癌的肿瘤生长和转移。⑥低表达NMI和高表达COX-2的肺癌患者生存较短预后较差，NMI是一个独立的预后因子。本研究揭示了肺癌中COX2高表达的分子机制，明确了NMI在肺癌细胞中生物学功能和作用机制，阐明了NMI表达和COX-2表达在肺癌中的临床意义，为肺癌的治疗提供了一个潜在的治疗靶点。在项目基金和相关基金的支持下，我们还在乳腺癌细胞中研究了NMI对hTERT基因表达的调控，我们发现NMI可以通过与转录因子YY1相互作用抑制hTERT启动子活性和基因表达。NMI可以通过抑制hTERT表达抑制乳腺癌干细胞特性和乳腺癌细胞的迁移能力进而抑制乳腺癌的生长和转移。乳腺癌肿瘤组织中NMI表达与hTERT表达呈负相关，低表达NMI并高表达hTERT的患者生存期较短预后较差。