基因组变异是肿瘤发生的内在因素，DNA损伤修复是维护基因组稳定的重要途径，其过程涉及多种修复蛋白从胞浆入核对发生损伤的DNA进行修复，一旦这类损伤修复基因变异或缺失将显著增加肿瘤的发生率。虽然目前对修复蛋白的生物化学机制及作用方式有了较深入的理解，然而关于这类蛋白是如何进入核内的、其明确的核转运分子机制是什么、它们是否有共同之处、以及是否可能以这类分子为靶点进行临床转化应用等均不清楚。本课题前期发现EHD2具有运输多种DNA修复蛋白入核的作用，EHD2基因敲除后小鼠的DNA损伤及成瘤显著增强。本项目拟在此基础上，结合乳腺癌中EHD2表达呈下调趋势这一临床现象，对EHD2行负调控的候选miRNA展开研究，阐明EHD2负调控机制及其在肿瘤发生中的作用。进而，一旦肿瘤发生后，其DNA损伤修复能力直接与其放射敏感性相关。因此，阐明EHD2的miRNA负调控机制还将有利于乳腺癌的分子诊断和疗效预测。

Carcinogenesis is primarily a result of genomic alteration due to failure of DNA damage repair (DDR), which involves groups of DDR proteins whose mutation or alteration will enhance tumorigenesis. Although the biochemistry mechanism and function of DDR proteins in the nuclei have been extensively explored, nuclear translocation of DDR proteins from cytoplasm remains to be elucidated. We found that a variety of DDR proteins were transported into the nuclei by EHD2 and knockout of it significantly promoted tumor growth. Based on the fact of a lower expression of EHD2 in breast cancer tissues, this project will focus on the mechanism study of EHD2 negative regulation by microRNA which will be useful for molecular diagnosis and therapeutic response prediction in breast cancer.