MKP-1对肺癌细胞合成代谢关键酶和抗氧化蛋白表达的影响及相关机制研究

Much of the mechanism by which MKPK signaling drives proliferation during oncogenesis is attributed to its regulation of the cell cycle. However, there are also bodies of evidence suggest that MAPK signaling directs another hallmark of tumorigenesis, namely Warburgh metabolism. MAPK phosphatase1 (mitogen-activated protein kinase phosphatases, MKPs, also known as DUSP1) which dephosphorylates MAPKs, plays an important role in the occurrence and progression of tumors and its resistance to drugs. Hepatic MKP-1 also has been shown to selectively regulate glucose metabolism and energy homeostasis, but its role in cancer metabolic reprogramming has not been investigated before. .. Nrf2 acts as a key regulator in protecting cells from oxidants and electrophilic reagents. Tumor cells hijack Nrf2 to promote metabolic activities that support cell proliferation in NSCLC cells. .. In our study we discovered that down-regulating MKP-1 in NSCLC A549 resulted in the inhibition of the expression of key enzymes in anabolic pathways, and also the expression of anti-oxidant proteins. As most of the genes affected are also regulated by Nrf2, we proposed that MKP-1/Nrf2 axis may play a role in regulating anabolic pathways in NSCLC... In this proposal we are aiming to investigate the role of MKP-1 in cancer metabolic reprogramming. The questions to be answered are:.1).MKP-1/Nrf2 axis in cancer metabolic reprogramming in NSCLC.2).Molecular mechanism of the interaction of MKP-1 and Nrf2.3).The clinical significance of the interaction of MKP-1 and Nrf2

MKP-1 是MAPK内源性的抑制蛋白， 其不仅参与调节细胞周期，而且参与调控细胞凋亡。.MKP-1还与肿瘤生长和耐药性密切相关。Nrf2调控Ⅱ相解毒酶和抗氧化蛋白的表达，肿瘤细胞"绑架"Nrf2系统调控肿瘤代谢重编程，促进癌细胞代谢和生长。.研究表明，肝细胞MKP-1选择性地调控葡萄糖代谢和能量稳态，但是MKP-1对肿瘤代谢重编程影响如何目前还是空白，本项目拟建立沉默MKP-1的非小细胞肺癌的体外细胞模型和在体裸鼠移植瘤动物模型；并对表型、基因表达谱和代谢进行差异分析；拟利用分子生物学和蛋白质化学等领域研究方法和手段研究MKP-1和Nrf2通路相关性及其对肿瘤代谢的影响；揭示MKP-1影响合成代谢关键酶和抗氧化蛋白表达机制; 建立临床肺癌肿瘤组织内MKP-1与Nrf2相关性以及与肿瘤发生、发展的关系。.此项目将为更有效治疗肺癌提供新的思路和方法。

MKP-1 是MAPK内源性的抑制蛋白， 其不仅参与调节细胞周期，而且参与调控细胞凋亡。MKP-1还与肿瘤生长和耐药性密切相关。Nrf2调控Ⅱ相解毒酶和抗氧化蛋白的表达，肿瘤细胞"绑架"Nrf2系统调控肿瘤代谢重编程，促进癌细胞代谢和生长。研究表明，肝细胞MKP-1选择性地调控葡萄糖代谢和能量稳态，但是MKP-1对肿瘤代谢重编程影响如何目前还是空白，本项目建立了沉默MKP-1的非小细胞肺癌的体外细胞模型和在体裸鼠移植瘤动物模型；并对表型、基因表达谱和代谢进行差异分析；利用分子生物学和蛋白质化学等领域研究方法和手段研究了MKP-1和Nrf2通路相关性及其对肿瘤代谢的影响；我们提出了MKP-1调控Nrf2的机制，具体为：MKP-1调控Nrf2不依赖于KEAP1， MKP-1与Nrf2直接相互作用而阻碍Nrf2泛素化降解，增加Nrf2蛋白稳定性和转录活性。另外， Nrf2通过与MKP1基因启动子上的ARE序列结合，在转录水平反馈上调MKP1。因此， MKP-1/Nrf2的相互作用促进了肺癌细胞的代谢重编程，肿瘤生长和耐药。本项目圆满完成了原计划中提出的任务和目标，为发现治疗癌症的新靶点、设计个性化治疗方案提供理论和实验依据。取得成果共24项，其中在Cancer Letter （IF6.5）, Hepatology （IF 14.9）, Free Radical Biology and Medicine（IF6.0，2篇）等国际主流杂志发表（共同）通讯作者论文12篇，其它论文5篇，论文被引用279次（含ISI高被引论文1篇）。该项目负责人还在2018年获浙江省自然科学二等奖一项（排名第一），项目申报专利2项，培养博士后一名，博士生3名。本人和博士后在国际学术会议分别作报告一次。