The Role of XBP1 During Hypoxia and Tumor Growth

描述(申请人提供)：低氧导致实体肿瘤的生理性内质网(ER)应激。先前的研究表明，低氧是抗癌治疗后局部、局部和远处复发的主要决定因素。虽然许多研究人员一直在研究缺氧诱导因子(HIF-1和HIF-2)介导的缺氧反应，但我们将探讨未折叠蛋白反应(UPR)--一种不依赖于HIF的信号通路--在肿瘤生长中的作用。UPR是一条进化上保守的途径，其功能是减少内质网中蛋白质的积累，从而增强对内质网应激的耐受能力。我们推测，由于UPR在缺氧时被激活，它可能是缺氧期间细胞存活的关键调节因子，对肿瘤生长是必要的。在这项研究中，我们将分析调控XBP1表达对肿瘤生长的影响，确定低氧对ER相关降解(ERAD)的影响，并研究XBP1靶基因EDEM(ER降解增强α-甘露糖苷酶样蛋白)在肿瘤生长中的作用。最终，这些研究不仅可能导致基于XBP1在肿瘤中的抑制的新型抗癌疗法的开发，而且还可能为我们理解肿瘤的发生提供基本的见解。

DESCRIPTION (provided by applicant): Hypoxia induces a physiologic endoplasmic reticulum (ER) stress in solid tumors. Previous studies have indicated that hypoxia is a major determinant of local, regional, and distant recurrence after anticancer therapy. While many investigators have pursued studies characterizing the hypoxia induced factor (HEF-1 and HIF-2) mediated response to hypoxia, we will investigate the role the unfolded protein response (UPR), a HIF-independent signaling pathway, on tumor growth. The UPR is an evolutionarily conserved pathway that functions to reduce protein accumulation in the ER resulting in an increased capacity to tolerate ER stress. We hypothesize that since the UPR is activated during hypoxia, it may be a critical regulator of cell survival during hypoxia and is necessary for tumor growth. In this proposal, we will analyze the effect of modulating XBP1 expression on tumor growth, determine the effect of hypoxia on ER associated degradation (ERAD), and investigate the role of an XBP1 target gene, EDEM (ER degradation enhancing alpha-manosidase-like protein) on tumor growth. Ultimately, these studies may not only lead to the development of novel anticancer therapies based upon inhibition of XBP1 in tumors, but may also provide fundamental insights into our understanding of tumorigenesis.