NLK的表达调控在Smad4介导非小细胞肺癌转移中的作用

项目名称： NLK的表达调控在Smad4介导非小细胞肺癌转移中的作用

项目编号： No.81472185

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 茅国新

作者单位： 南通大学

项目金额： 72万元

中文摘要： TGF-β/Smads通路介导的上皮间质转化(EMT)被认为是引发非小细胞肺癌（NSCLC）转移的主要分子机制。本课题组前期研究首次发现Nemo样激酶（NLK）对Smad4的磷酸化可促进其出核并抑制TGF-β通路的活化，并且NSCLC组织中NLK低表达与淋巴结转移相关，而microRNA-221（miR-221）可以靶向抑制NLK的表达。在此基础上，课题组拟分析miR-221诱导NLK表达下调的明确机制，进而分析这一机制对Smad4的活性和TGF-β诱导的EMT促进作用。最后，拟在NSCLC裸鼠动物模型中研究miRNA-221、NLK的表达和EMT及转移的关联性。本研究将探讨miR-221调节的NLK表达下调，对促进TGF-β/Smad4介导的下游靶基因的转录和EMT形成的影响，研究有助于阐明NSCLC转移的分子机制，并为NSCLC的治疗提供新的途径。

中文关键词： C05_气管；支气管；肺肿瘤；上皮间质转化；Smad4；微小RNA-221；Nemo样激酶

英文摘要： Epithelial-mesenchymal transition (EMT), mediated by a variety of oncogenic signaling pathways, such as TGF-β/Smads signaling, was regarded as a key molecular mechanism underlying non-small cell lung cancer(NSCLC) metastasis. In the present study, we found that Nemo-like kinase(NLK)-mediated Smad4 phosphorylation could promote the nuclear export of Smad4 and prevent the hypo-activation of TGF-β signaling. Besides, the expression of NLK was negtively correlated with lymph node metastasis, whereas microRNA-221 (miR-221) could repress the level of cellular NLK. Based on these findings, we aim to analyze the precise mechanism of miR-221-mediated down-regulation of NLK. Furthermore, the role of miR-221-induced down-regulation of NLK in the regulation of Smad4 activity and TGF-β-induced EMT will be evaluated. Finally, we will investigate the association between the expression of miR-221 and NLK with the formation of EMT in nude mouse model. We aim to determine the influence of downregulated NLK by miR-221 in NSCLC on the expression of TGF-β targeting genes and TGF-β-mediated EMT progress. Our investigation might help clarify the molecular mechanism of NSCLC metastasis, and provide potential opportunity into NSCLC therapy.

英文关键词： lung cancer;epithelial mesenchymal transition;Smad4;microRNA-221;Nemo-like kinase