丰富生存环境通过ABC转运蛋白调控胰腺癌化疗敏感性的作用及机制研究

项目名称： 丰富生存环境通过ABC转运蛋白调控胰腺癌化疗敏感性的作用及机制研究

项目编号： No.81502601

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 袁慧

作者单位： 上海交通大学

项目金额： 18.5万元

中文摘要： 化疗药物治疗是目前胰腺癌治疗主要手段之一，如何增强其化疗增敏性是胰腺癌研究中的重要课题。丰富生存环境(Enriched Environment，EE)是一种可靠的良性心理应激动物模型。我们的研究证实EE对胰腺癌具有显著的抑制作用。有趣的是，前期研究还发现，EE能显著提高5-氟尿嘧啶(5-FU)或吉西他滨(GEM)对胰腺癌的疗效，表明增强了上述化疗药物的敏感性。对肿瘤组织的全基因组表达谱分析发现，EE能下调多个ATP-binding cassette(ABC)转运蛋白，而ABC转运蛋白与肿瘤化疗敏感性密切相关，提示其可能介导了EE增强胰腺癌化疗敏感性的作用。本项目将在此基础上，鉴定出EE增强胰腺癌化疗敏感性作用中关键的ABC转运蛋白，并进一步探讨EE通过其调控胰腺癌化疗敏感性的机制。本项目的开展将为良性心理应激调节胰腺癌化疗敏感性提供相关实验依据，并可为提高胰腺癌化疗的辅助治疗提供新的思路。

中文关键词： C11_胰肿瘤；丰富生存环境；化疗敏感性；ABC转运蛋白

英文摘要： Chemotherapy is one of the main treatments for pancreatic cancer. Due to the low chemosensitivity of pancreatic cancer patient, there is an urgent need for the development of novel strategies for enhancing its chemosensitivity. Enriched Environment (EE) housing is a reliable animal model of eustress psychological stress. Recently, it has been demonstrated that EE can significantly inhibit the growth of pancreatic cancer. Interestingly, we also found that the therapeutic efficacy of 5-fluorouracil (5-FU) or gemcitabine (GEM) for pancreatic cancer was significantly improved in EE-housed mice. Meanwhile, EE exposure significantly enhanced the chemosensitivity of pancreatic cancer cells. Further, the genome-wide microarray expression analysis of tumor tissues found that EE significantly down-regulated the expression of a number of ATP-binding cassette (ABC) transporters, which play an important role in cancer chemosensitivity, suggesting that EE enhances the sensitivity of pancreatic cancer to chemotherapeutic drugs via regulating the expressing of ABC transporters. Based on our previous studies, the present research project will identify the key ABC transporter(s) contributing to the EE-induced enhancement of pancreatic cancer chemosenstivity. Further, we will investigate the mechanism by which EE regulates the expression of ABC transporters to enhance chemosensitivity of pancreatic cancer. The project will provide experimental evidence demonstrating the regulatory effects of eustress psychological stress on pancreatic cancer chemosensitivity. In addition, it will open the way toward novel combination therapy strategies for improving prognosis in pancreatic cancer patients.

英文关键词： Pancreatic Cancer;Enriched Environment; Chemosensitivity;ABC Transporters