抑癌作用基因PTPRD抑制低氧应激反应及其调控机制的研究

项目名称： 抑癌作用基因PTPRD抑制低氧应激反应及其调控机制的研究

项目编号： No.81201552

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 胡东

作者单位： 华中科技大学

项目金额： 23万元

中文摘要： 众多的肿瘤如肺癌、胶质母细胞瘤、结肠癌等中均发现了较高频率的酪氨酸磷酸酶受体PTPRD的缺失、突变或基因甲基化失活。PTPRD已成为最具潜力的抑癌基因研究对象之一，但抑癌机制不明。前期工作中，我们发现PTPRD在低氧而非正常氧浓度下显著抑制肿瘤细胞生长。因此，PTPRD极有可能通过抑制肿瘤低氧应激反应机制发挥其抑癌作用。为阐明这一机制，首先，我们将建立肿瘤的PTPRD重建表达及基因敲弱模型，并在多个细胞模型中确立PTPRD在低氧环境中的抑癌作用。其次，我们将在低氧环境下研究PTPRD对肿瘤细胞代谢、自噬及凋亡的影响，以及分子水平对HIF1α，mTOR，AMPK及UPR等关键反应调节通路的影响。最后，将综合细胞和分子水平的结果，深入研究其调控分子和细胞机制间的联系。对PTPRD调控低氧应激反应这一新的抑癌机制的阐明，将促进对肿瘤发病机理的了解，为肿瘤分子病理分型及个体化治疗提供新的理论依据。

中文关键词： PTPRD；低氧；肿瘤代谢；凋亡；自噬

英文摘要： Deletion, somatic mutation and/or epigenetic inactivation of protein tyrosine phosphatase receptor delta（PTPRD） have been reported to occur frequently in several malignancies such as lung adenocarcinoma, glioblastoma and colorectal cancer, suggesting it's a tumor suppressor gene. However, the mechanisms underlying its tumor suppressive role remains elusive. In our preliminary data, restoring wildtype (Wt) PTPRD to several PTPRD-deficient cancer cell lines suppresses the cell proliferation and survival significantly under hypoxia stress condition, however, does not do so under normoxia condition. Together with other evidence, we propose that PTPRD is an important regulator that modulating hypoxia energy stress responses, through which PTPRD exhibit its tumor suppressive role in vivo. The overall goal of our project is to clarify the mechanisms by which PTPRD regulates hypoxia stress response in cancer cells at cellular and molecular level. Our specific aims include: 1. To establish the Wt PTPRD restoration models in various PTPRD-deficient cancers and knockdown models in cancers with Wt PTPRD expression and to examine the capacity of PTPRD in suppressing cell survival and tumorigenicity under hypoxia stress. 2. To assay the effects of PTPRD on cell metabolism, autophagy, apoptosis and cell cycle under hypoxia and

英文关键词： PTPRD；hypoxia；cancer metabolism；apoptosis；autophagy