NDRG1促进非小细胞肺癌干细胞自我更新的分子机制研究

Cancer stem cells (CSCs) are responsible for lung cancer initiation, metastasis, recurrence and Chemoresistance. Self-renewal, the key ‘stemness’ property of CSCs, is the breakthrough of CSCs-targeted therapy. By using mRNA microarray analysis, we found a potential target of self-renewal of NSCLC stem cells –NDRG1. It has been identified that NDRG1 was over-expressed in lung cancer, but little was known about its cancerigenic mechanism and there was no study about the role of NDRG1 played in Self-renewal of CSCs.We previously described that NDRG1 was aberrantly expressed in NSCLC stem cells and promoted the self-renewal of CSCs, but its subtrate and molecular mechanism are unclear. In this project we will：employ in vitro assay of sphere initiation and in vivo assay of tumor formation to assess the role of NDRG1 in the self-renewal of NSCLC stem cells; utilize the Cignal™ Reporter System and Co-IP to identify the molecular mechanism for NDRG1 promoting NSCLC stem cells self-renewal; collect NSCLC samples to establish the relationship among NDRG1, its substrate and prognosis. Our study will provide a novel therapeutic target for NSCLC stem cells.

肿瘤干细胞是肺癌发生、转移、复发与耐药重要原因之一。干细胞的自我更新是其最关键的“干性”特征，也是靶向清除肺癌干细胞的突破口。我们通过mRNA表达谱芯片筛选到非小细胞肺癌干细胞自我更新的潜在调节因子——NDRG1。目前为止国际上没有关于NDRG1在肿瘤干细胞自我更新中的研究报道。我们在前期工作中发现NDRG1在非小细胞肺癌干细胞中异常高表达并促进肿瘤干细胞自我更新，但其靶蛋白和分子机制尚不明确。为此，本课题拟在先前研究基础上：体内体外实验明确NDRG1调控非小细胞肺癌干细胞自我更新；信号通路分析工具Cignal™ Reporter System及免疫共沉淀等技术明确NDRG1促进非小细胞肺癌干细胞自我更新分子机制；免疫组化染色检测手术切除肺癌患者石蜡标本中NDRG1及其靶蛋白的表达与分布，分析NDRG1及其靶蛋白的表达量与患者预后的相关性。本研究将为非小细胞肺癌干细胞定向清除提供新的治疗靶

肿瘤干细胞是肺癌发生、转移、复发与耐药重要原因。干细胞的自我更新是其最关键的“干性”特征，也是靶向清除肺癌干细胞的突破口。目前为止国际上没有关于NDRG1在肿瘤干细胞自我更新中的研究报道。我们研究发现NDRG1在非小细胞肺癌干细胞中表达增高。进一步通过构建的NDRG1高表达/低表达的细胞株进行体内外实验发现，NDRG1是一个新的促进非小细胞肺癌自我更新调控的蛋白，且NDRG1通促进c-Myc的表达从而促进非小细胞肺癌干细胞的干性特征。本课题的研究结果提示NDRG1是靶向清除肺癌干细胞的潜在靶点。