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

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.

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。

胰腺癌患者五年生存率低于3%，被认为是病死率高的肿瘤之一。由于缺乏临床症状及早期的检测方法，仅有10%-15%的患者能在早期被诊断接受手术治疗，因此胰腺癌患者平均生存时间则小于6个月 。对大多数中晚期胰腺癌患者而言，化疗是目前临床采用的主要治疗措施，但化疗后平均生存时间也只能延长5周左右，导致化疗效果不良的一个主要原因是由于化疗耐药性，它是目前困扰胰腺癌化疗的重大难题。研究证实EE作为一种良性心理应激模型，能促进肿瘤对化疗药物的敏感性，从而协同增强化疗药物的疗效。研究发现ABC家族转运蛋白的ABCA8b能够调控肿瘤对化疗药物的敏感性。用吉西他滨不同浓度以及时间处理胰腺癌细胞后，ABCA8表达水平明显升高（P＜0.05），并且有一定的剂量和时间反应关系。过表达ABCA8能够明显增强对胰腺癌PANC1和CFPAC1细胞迁移能力（P＜0.01）。体内实验表明ABCA8够抑制胰腺癌PANC1细胞对GEM的反应性（P＜0.05），并可以抑制GEM介导的细胞凋亡。同时，ABCA8可以上调抗凋亡蛋白Bcl2的表达以及下调促凋亡相关蛋白Bax的表达。本项目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