MDM2介导TOP2A的表达调节对阿霉素敏感性的影响

Doxorubicin, a topoisomerase IIα (Top2A) inhibitor, is currently a key chemotherapeutic agent of anti-neoplastic drugs used in clinical practice. Top2A expression levels are a major determinant of response to doxorubicin. Our studies in neuroblastoma cells showed that the expression level of MDM2（murine double minute 2）was related to sensitivity of tumor cells to doxorubicin, and the high expression of MDM2 promoted TOP2A expression. It indicated MDM2 may be involved in the sensitivity of doxorubicin through regulating the TOP2A expression, but the mechanism is still to be explored. Our further studies demonstrated that MDM2 could bind to the TOP2A mRNA. Therefore, this project will further investigate the molecular mechanism about how MDM2 regulate the expression of TOP2A and the effect of TOP2A expression mediated by MDM2 on doxorubicin sensitivity in neuroblastoma cells and animal models by using vector construction, gene transfection and RNA interference technology. This study will identify a new signal pathway involved in doxorubicin sensitivity, which may be an effective intervention target.

拓扑异构酶IIα（TOP2A）抑制剂阿霉素是多种肿瘤化疗中最重要的一线药物，肿瘤对阿霉素是否敏感主要取决于TOP2A的表达水平。我们在神经母细胞瘤的研究中发现MDM2的表达水平与肿瘤细胞对阿霉素的敏感性有关，MDM2的高表达促进了TOP2A的表达，提示MDM2可能通过调节TOP2A的表达而介导阿霉素的敏感性，但其机制尚待探讨。我们进一步的研究表明MDM2可与TOP2A的mRNA结合。因此，本项目拟采用载体构建﹑基因转染及RNA干扰等技术，在神经母细胞瘤细胞及动物模型中进一步探讨MDM2对TOP2A表达调节的分子机制、MDM2介导TOP2A的表达调节对阿霉素敏感性的影响及其机制。本研究将鉴定MDM2对TOP2A的表达调节为介导阿霉素敏感性的新型信号途径，可能成为一个有效干预靶点。