PPARγ外源激动剂早期干预NNK诱导肺癌干细胞中15-LOX表达调控的机制

项目名称： PPARγ外源激动剂早期干预NNK诱导肺癌干细胞中15-LOX表达调控的机制

项目编号： No.81472742

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： 李明月

作者单位： 香港中文大学深圳研究院

项目金额： 72万元

中文摘要： 我们发现尼古丁衍生物NNK诱导小鼠非小细胞肺癌过程中, PPARγ的内源激动剂水平的降低先于肿瘤出现；并且在NNK诱导肺组织出现超常增生肥大初期用PPARγ 外源性激动剂吡格列酮（PGZ）进行早期干预，可激活PPARγ从而抑制肺癌发生。然而，PPARγ 外源性激动剂抑制肺癌的早期干预机制有待深入研究。进一步的研究发现PGZ可保持其内源性激动剂代谢酶15-LOX的水平；NNK刺激的肺癌细胞中CD-133、ALDH1A1等肺癌干细胞标记物表达显著上调。从而我们提出PPARγ外源激动剂PGZ 可通过调控NNK诱导肺癌干细胞中15-LOX的表达而抑制肿瘤发生。本课题拟建立PGZ早期干预NNK诱导肺细胞超常增生肥大进一步发展成肺癌过程中肺癌干细胞形成的小鼠模型，在转录及翻译水平上探讨15-LOX基因于肺癌干细胞生成过程中的表达调控机制，为PGZ及其调控的分子应用于肺癌早期干预奠定理论基础。

中文关键词： C05_气管；支气管；肺肿瘤；肺癌干细胞；PGZ；早期干预；15-LOX；基因表达调控

英文摘要： Our previous studies have demonstrated that the reduced levels of endogenous ligands of peroxisome-proliferator activated receptor γ(PPARγ), occur before the formation of NSCLC induced by smoking carcinogens NNK in mice. On the other hand, we found that the application of Pioglitazone (PGZ), a synthetic PPARγ ligand, at the early phage of alveolar hyperplasia formation induced by NNK, was able to prevent NNK-induced lung tumor development through activation of PPARγ. Further studies confirmed that PGZ prevented NNK-induced lung tumor development by maintaining the level of 15-LOX and thatNNK stimulated the expression of cancer stem cell markers such as ALDH1A1 and CD133. Based on our previous studies, the aim of this proposal is to study how PGZ interferes with the NNK-induced early phage of alveolar hyperplasia formation via regulating 15-LOX at transcriptional and translational levels in A/J mice, and to explore how the PGZ-mediated treatment affects the development of lung cancer stem cells . The Data obtained should help us to understand the 15-LOX in lung cancer stem cell development and enable us in a position much closer to establish the effective early therapeutic protocol for NSCLC by PGZ.

英文关键词： Lung cancer;lung cancer stem cell;PGZ early prevention;15-LOX;gene expression and regulation