The Role of XBP1 During Hypoxia and Tumor Growth

描述（由申请方提供）：缺氧诱导实体瘤中的生理性内质网（ER）应激。 以往的研究表明，缺氧是抗癌治疗后局部、区域和远处复发的主要决定因素。 虽然许多研究人员已经进行了表征缺氧诱导因子（HEF-1和HIF-2）介导的缺氧反应的研究，但我们将研究未折叠蛋白反应（UPR），一种HIF非依赖性信号通路，对肿瘤生长的作用。 UPR是一种进化上保守的途径，其功能是减少ER中的蛋白质积累，导致耐受ER应激的能力增加。 我们推测，由于UPR在缺氧期间被激活，它可能是缺氧期间细胞存活的关键调节因子，并且是肿瘤生长所必需的。 在这项提案中，我们将分析调节XBP 1表达对肿瘤生长的影响，确定缺氧对ER相关降解（ERAD）的影响，并研究XBP 1靶基因EDEM（ER降解增强α-腺苷酸酶样蛋白）对肿瘤生长的作用。 最终，这些研究不仅可能导致基于抑制肿瘤中的XBP 1的新型抗癌疗法的开发，而且还可能为我们理解肿瘤发生提供基本见解。

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.