长非编码RNA介导乳腺癌辐射抵抗及其分子机制研究

项目名称： 长非编码RNA介导乳腺癌辐射抵抗及其分子机制研究

项目编号： No.81502664

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 崔明

作者单位： 中国医学科学院

项目金额： 19万元

中文摘要： 我国乳腺癌的发病率与致死率均超过全球平均水平。放疗是治疗乳腺癌惯用的手段，但流行病学研究显示不少乳腺癌患者表现出辐射耐受，导致治疗效果不佳。长非编码RNA（lncRNA）是分子生物学领域的研究热点，报道指出lncRNA在个体生理和病理的进程中发挥着重要的作用。基于此，本课题以乳腺癌为模型，主要探讨lncRNA HOTAIR在乳腺癌辐射抵抗中的作用并揭示其具体分子机制。实验拟应用分子克隆、报告基因、流式细胞术等分子生物学技术，验证HOTAIR在乳腺癌细胞辐射抵抗中的作用，并阐明其激活的信号通路及具体作用方式。结合临床标本验证HOTAIR与下游基因在乳腺癌组织中的相关性，并结合回访资料探讨HOTAIR与乳腺癌患者放疗预后的关系。最后运用裸鼠成瘤模型佐证上述结果。本研究将揭示lncRNA在肿瘤细胞辐射抵抗中的作用，并为乳腺癌个体化治疗提供新的依据和治疗靶点。

中文关键词： 乳腺肿瘤；放射治疗；辐射抵抗；长非编码RNA；HOTAIR

英文摘要： Breast carcinoma is a leading cause of cancer deaths among women every year worldwide. Radiotherapy is adopted as a commonly used therapy for patients with breast cancer. Heretofore, mounting clinical and epidemiological studies have reported that patients with breast neoplasms exhibit remarkably radioresistance, resulting in poor prognosis. However, the underlying mechanism remains largely unknown. HOX transcript antisense RNA (HOTAIR), as a long non-coding RNA, has been associated with a spectrum of biological functions and the disruption of these functions play a critical role in the development of cancer. It has been reported that HOTAIR is overexpressed in various cancer, such as breast carcinoma. Nevertheless, whether HOTAIR underpins the radioresistance of breast cancer is still enigmatic. Thus, we aim to explore whether HOTAIR contributes to the radioresistance of breast cancer cells. Our previous observation reveals that HOTAIR is able to strengthen the radioresistance of breast cancer cells in vitro. In addition, HOTAIR up-regulates the mRNA and protein levels of HSP70 in breast cancer cells in a dose-dependent fashion treated with radiation. These results give us a clue to hypothesize that HOTAIR indeed involves in the radioresistance of breast carcinoma cells. Therefore, we further seek to investigate the molecular mechanism by which HOTAIR enhances the radioresistance of breast cancer cells. We also would like to validate our conclusions using mouse models as well as clinical breast cancer tissues. Our finding will provide new insights into the mechanism of breast cancer radioresistance and a novel target for individual therapy of breast cancer patients.

英文关键词： Breast cancer;Radiotherapy;Radioresistance;Long non-coding RNA;HOTAIR