smoothened介导的gpcr样信号对肿瘤多药耐药细胞生物学特性的影响及作用机制研究

《smoothened介导的gpcr样信号对肿瘤多药耐药细胞生物学特性的影响及作用机制研究》由会员上传分享，免费在线阅读，更多相关内容在学术论文-天天文库。

1、後旦大学万方数据复旦大学硕士研究生学位论文Smoothened介导的GPCR样信号对肿瘤多药耐药细胞生物学特性的影响及作用机制研究院系(所)：专业：姓名：指导教师：完成日期：药学院药理学L目争白霞谭文福副研究员2013年5月20目万方数据目录一、缩略词表······················································．1二、中文摘要·······················································3三、英文摘要·························

2、······························5四、研究背景·······················································7五、正文···························································9第一部分Smoothened介导的GPCR样信号对肿瘤多药耐药的影响1．1弓l一言························································91．2材料与方法·············

3、····································101．3结果·······················································141．4讨{仑·······················································25第二部分INK信号通路通过调控Snail和twistl维持肿瘤多药耐药细胞的间质特征2．1引言············一·········································282．2材料与方法··

4、···············································292．3结果·······················································322．4讨{仑·······················································39六、结论···························································41七、参考文献·······························

5、························42八、致谢···························································49万方数据复旦大学硕士学位论文缩略词表缩略符外文全称中文全称万方数据复旦大学硕士学位论文2万方数据复旦大学硕士学位论文中文摘要多药耐药(multidrugresistance，MDR)的发生是导致肿瘤化疗失败的主要原因。研究表明肿瘤多药耐药细胞不仅具有对化疗药物耐药的生物学特性，其相对化疗敏感的肿瘤细胞具有更强的转移能力。Hedgehog(Hh)是一种高度保守的信号通路

6、，在诸多生物种类的胚胎发育、组织稳态的维持中发挥着重要作用。Hh信号通路的异常活化与多种肿瘤的发生、发展密切相关。研究还发现Hh信号通路能促进多药耐药的发生。Hh信号通路的关键信号转导分子Smo具有与G蛋白偶联受体类似的结构，提示其可能具有GPCR样的信号转导特征。有研究证实在C18果蝇细胞、Sf9细胞及NIH3T3细胞中，Smo能够与God偶联，并激活下游转录因子Gli。但是，Gai在Hh信号通路转导中的作用仍存在很大争议，尚存诸多亟待阐明之处。借助细胞、分子生物学手段，本论文首先以多药耐药细胞K562／A02、KB／VCR及其对应的亲本细胞K

7、562、KB为研究对象，阐述了在肿瘤耐药细胞中Smo的GPCR样信号转导特征。我们发现在以自分泌激活方式导致的异常Hh信号通路活性的肿瘤耐药细胞K562／A02、KBⅣCR中，Smo能够通过God激活Hh信号通路中转录因子Gli，以维持K562／A02、KB／VCR的耐药性状；更重要的是，我们的实验结果证实Gp丫亚基与Gai分离后，能通过JNK激活转录因子Gli的活性，进而维持肿瘤耐药细胞的耐药性状。我们的这些结果进一步在借助Smo异常激活突变体(SmoAl)而人为(artificial)激活Hh通路活性的化疗敏感细胞KB、K562中再现，从而充

8、分阐明了在肿瘤耐药细胞中Smo的GPCR样信号转导特征：Smo能通过偶联Gai，激活转录因子Gli的活性，进而促进多药耐药的发生；而且，