印记基因PHLDA2调控骨肉瘤放疗增敏作用及机制研究

项目名称： 印记基因PHLDA2调控骨肉瘤放疗增敏作用及机制研究

项目编号： No.81201756

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： 李懿

作者单位： 中国人民解放军总医院

项目金额： 23万元

中文摘要： 骨肉瘤的放疗抵抗是制约其疗效提高的主要因素。凋亡相关基因影响辐射敏感性，但凋亡相关的印记基因在肿瘤放疗增敏中的作用尚不清楚。我们前期研究发现，印记基因PHLDA2在骨肉瘤中发挥促凋亡作用，其表达水平与放疗疗效正相关；结合文献报道，PHLDA2的PH结构域能与Akt分子竞争性结合PIP位点。我们推测，上调骨肉瘤中PHLDA2印记基因的表达增加骨肉瘤细胞的放射敏感性，其敏感性的增加是通过与X射线协同抑制Akt蛋白的激活实现的。本研究拟采用Tet调控的真核表达载体技术，在骨肉瘤大体标本、细胞株及动物模型上，观察PHLDA2表达与放疗疗效的相关性，并对PHLDA2基因增敏放疗的分子机制进行研究，以期阐明上调PHLDA2基因表达的辐射增敏作用及相关的增敏机制，为预测骨肉瘤的放疗疗效提供有用的分子靶点，同时为基因靶向的辐射增敏治疗提供部分新的线索和实验依据。

中文关键词： 放射治疗；骨肉瘤；印记基因；PHLDA2；AKT

英文摘要： Radiation resistance may be a predominant factor with poor efficacy of osteosarcoma therapy.Apoptosis-related genes can affect a tumor's response to radiation,however the role of apoptosis-related imprinted genes in radiosensitivity is unresolved. Our previous studies have shown that the imprinted gene PHLDA2 may be a pro-apoptotic factor in osteosarcoma,and the expression may be associated with increased radiation response.Literatures indicate that the PH domain of PHLDA2 binds to PIP site competitively with Akt.We therefore hypothesize that overexpression of PHLDA2 may contribute to increase the sensitivity of radiation in osteosarcoma,which is achieved by synergistic inhibition of Akt with X-Ray.In this research,the corelation between PHLDA2 and radiation response has been investigated in osteosarcoma specimens,cell lines and animal models, meanwhile the molecular mechanism of radiosensitivity has also been studied.The aim of this study is to clarify the effect of PHLDA2 overexpression on increasing the sensitivity of radiation and the relative mechanism, which can provide a new target to predict the radiation response of osteosarcom,and also provide some new experimental basis for enhancing radiasensitivity by targeted some genes.

英文关键词： radiotherapy；osteosarcoma；imprinted gene；PHLDA2；AKT