兰州大学机构库 >生命科学学院
Notch信号通路关键因子的表达及受体阻断对胃癌细胞生物学行为的影响
Alternative TitleThe expression of the key factor of Notch pathway and effects of Notch receptor-blocker on gastric cancer cells
何雯婷
Thesis Advisor李玉民
2011-12-01
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name博士
Keyword胃癌 Notch信号通路 幽门螺旋杆菌
Abstract本研究采用免疫组化、RT-PCR和Western Blot等方法,分析Notch信号通路受体、配体以及靶基因在胃癌发生发展中表达水平的变化;通过抑制Notch通路研究胃癌细胞生物学行为的改变,以确定Notch通路在胃癌发生中的作用。在明确Notch通路在胃癌中异常活化的基础上,选择胃癌最重要的高危因素——H. pylori,研究H. pylori感染胃正常粘膜细胞后对Notch信号通路的影响,探讨H. pylori感染致癌的可能机制。 研究结果表明,受体Notch 2和配体Jagged 1在病变组织中的表达显著增高,体外实验结果证实Notch 2和配体Jagged 1、Dll 4在胃癌细胞株中的mRNA水平和蛋白水平较正常胃粘膜细胞升高,而Notch 1及其活化形式NICD 1在两者之间差异不显著,提示在胃癌发生过程中受体Notch 1可能未参与促癌进程。使用γ酶抑制剂阻断Notch受体活化后,胃癌细胞发生凋亡,同时细胞增殖受到明显抑制。虽然使用抑制剂后表现为抑制细胞增殖,但是PI3K/AKT途径却没有明显变化。研究Notch配体发现Jagged 1、Dll 4表达水平变化不一致,Jagged 1变化无明显差异,Dll 4成显著性升高,我们推测在胃癌中Notch信号通路存在非依赖受体途径,配体自身通过相似剪切后激活的下游事件可能拮抗Notch受体途径的作用。胃癌高危因素H. pylori感染,使得正常胃粘膜细胞发生空泡性样变,细胞增殖受到抑制,RT-PCR结果显示感染后Notch信号通路的受体、配体和靶基因的表达都出现了上升,证明H. pylori感染可激活Notch信号通路。 总之,本研究发现Notch信号通路在胃癌中存在异常活化,Notch 1可能未参与促癌进程;抑制Notch受体可诱导胃癌细胞凋亡,抑制细胞增殖,同时可能激活了Notch非依赖受体途径,拮抗Notch受体途径的作用使得PI3K/AKT途径并未发生明显变化。另外,胃癌高危因素H. pylori感染可激活Notch信号通路,这可能是其致癌机制之一。因此,Notch受体抑制剂是胃癌的一种潜在靶向治疗药物。
Other AbstractIn this study, the expression of Notch signaling receptors, ligand and target gene in the development of gastric cancer were analysized by immunohistochemistry, RT-PCR, Western Blot and other methods. And to determine the role of Notch pathway in gastric cancer, we observed the biological behavior of gastric cancer cells with Notch inhibitor- GSI. In addition, we studied the relationship of Notch pathway and H. Pylori- the most important risk factor for gastric cancer. The results showed that the expression of receptor Notch 2 and ligand Jagged 1 was significantly higher in cancer tissues than the normal tissues. It was confirmed the mRNA and protein levels of Notch 2 and Jagged 1, Dll 4 increased in gastric cancer cell lines. However, the expression of Notch 1 was no significant difference between tumor cell lines and normal cell. It was suggesting that Notch 1 receptor may not be involved in the process of gastric cancer. Gastric cancer cell could be induced to apoptosis with γ – enzyme, and cell proliferation was inhibited at the same time. It is intresting that there is no significantly difference of PI3K/AKT pathway between them. Meanwhile we found Dll 4 expression levels increased after the cell treated with GSI. It was suggested that Notch ligand-independent pathway exists in gastric cancer and it has opposing effects with Notch receptor pathway. In other hand, cell proliferation was inhibited with H. pylori infection. It showed that all of Notch receptor, ligand and target gene expression increased by RT-PCR. In conclusion, this study found that Notch signaling pathway has abnormal activation in gastric cancer. Notch 1 may not be involved in tumor promotion process. Inhibiting Notch receptor can induce apoptosis and inhibit cancer cell proliferation, and it may activate the Notch ligand-independent way. In addition, H. pylori infection can activate the Notch signaling pathway, which may be one of the carcinogenic mechanisms. Thus, Notch receptor inhibitor could be a potential targeted medicine.
URL查看原文
Language中文
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/221916
Collection生命科学学院
Recommended Citation
GB/T 7714
何雯婷. Notch信号通路关键因子的表达及受体阻断对胃癌细胞生物学行为的影响[D]. 兰州. 兰州大学,2011.
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