TCTP在乳腺癌干细胞辐射抵抗中的作用及机制研究

项目名称： TCTP在乳腺癌干细胞辐射抵抗中的作用及机制研究

项目编号： No.31270899

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 张杰

作者单位： 中国人民解放军第四军医大学

项目金额： 75万元

中文摘要： 肿瘤干细胞（CSCs）是放疗后肿瘤复发的根源，有别于正常/肿瘤细胞的异常DNA损伤反应（DDR）是导致CSCs放疗逃逸的主要原因，机制不祥。研究发现，TCTP可能与乳腺癌干细胞（BCSCs）的异常生物学行为密切相关。我们首次研究证实，TCTP作为正常/肿瘤细胞DDR体系的关键分子直接参与DNA损伤修复，随着损伤程度加重，TCTP还通过自身表达量的"先增后降"与p53协同调节细胞凋亡反应。然而，高剂量辐照后，BCSCs内TCTP表达却持续增高，提示其相关DDR调控可能发生异常。本课题首次以BCSCs为对象，从细胞-动物-临床标本多个层面阐明TCTP与BCSCs辐射抵抗的相关性，利用基因转染、Co-IP等技术手段全面揭示TCTP在BCSCs辐射抵抗中的效应通路，并围绕ATM-TCTP-p53调控深入开展相关分子机理研究。项目实施对于揭示CSCs异常辐射抗性机制，寻找新的放疗靶点具有重要意义。

中文关键词： 肿瘤翻译控制蛋白；重编程；治疗抗性；转录因子；

英文摘要： Cancer stem cells (CSCs) have been postulated recently as responsible for recurrent tumours after radiotherapy. While the specific mechanism underlying radiation resistance of CSCs has not been fully elucidated, early data suggest differences in DNA repair, reactive oxygen species and survival signaling. Current studies indicate that the higher capability to repair DNA lesions is one of the major reasons for the resistance of Breast Cancer Stem Cells (BCSCs) to radiotherapy. However, the unique mechanisms of DNA repair pathways of BCSCs are unknown. The Translationally Controlled Tumor Protein (TCTP) is essential for survival by yet incompletely defined mechanisms. In general, it is thought that TCTP promotes cell viability through an anti-apoptotic role. Our study (PNAS, in press) have identified that TCTP supports the survival and genomic integrity of irradiated cells through a critical role in the DNA damage response (DDR). Upon exposure of normal human cells/tumor cells to low/mild dose γ rays, the TCTP protein level was greatly increased, with a significant enrichment in nuclei. TCTP up-regulation occurred in a manner dependent on ATM- and the DNA-dependent protein kinase (DNA-PK), and was associated with protective effects against DNA damage. Conversyly, high dose exposure led to decreased levels of TCTP

英文关键词： TCTP；Reprogramming；Therapy resistance；Transcription factors；