氧化亚铜纳米粒抑制恶性黑色素瘤转移的分子机制研究

项目名称： 氧化亚铜纳米粒抑制恶性黑色素瘤转移的分子机制研究

项目编号： No.81472771

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨庆

作者单位： 中国人民解放军第二军医大学

项目金额： 64万元

中文摘要： 黑色素瘤高度恶性，具有极强的增殖和转移能力，常规治疗方法的效果均不理想。纳米抗肿瘤药物具有肿瘤靶向性等优点，为肿瘤治疗提供了新的思路。本课题组将中医学与纳米科学有机地结合起来，首次报道氧化亚铜纳米粒（Cuprous oxide nanoparticles，CONPs）可显著抑制黑色素瘤转移，并启动线粒体凋亡通路选择性诱导肿瘤细胞凋亡等原创性成果，揭示了CONPs在黑色素瘤治疗中良好的应用前景。在前期研究的基础之上，本项目将利用循环肿瘤细胞提取系统、单细胞转录组测序等先进方法对肿瘤原发灶、循环肿瘤细胞、肺转移灶相关生物学指标进行检测，探讨CONPs对肿瘤新生血管及上皮/间充质转化调控网络的干预作用，并发现CONPs作用的关键基因，以阐明CONPs抑制黑色素瘤转移的分子机制和作用的关键信号通路，为深入了解无机纳米药物抗肿瘤转移的机制及开发同类纳米抗肿瘤药物提供有意义的参考。

中文关键词： C20_皮肤及黑色素瘤；氧化亚铜纳米粒；纳米药物；肿瘤转移

英文摘要： Melanoma is highly aggressive, leaving untreated patients with a median survival of less than 12 months, which is difficult to cure by conventional therapy methods. In recent years, the incidence rate of melanoma has been increasing rapidly, and more than 20,000 new patients are diagnosed with melanoma every year in China. It is greatly necessary to develop new methods and new drugs. With the fast development of nanoscience and nanotechnology, many nanomedicines show anti-tumor pharmacological effects, which can target the tumor tissue and show low systemic toxicity. Nanomedicine has been emerging as one of these new treatment options. Combining the nanoscience and traditional Chinese medicine, our previous research firstly discovers that cuprous oxide nanoparticles (CONPs) show anti-melanoma pharmacological effects obviously. CONPs can inhibit the metastasis and invasion of melanoma in vitro and in vivo, which is a significant pharmacological character for the therapy of melanoma, and it is of great meaning to explore the anti-metastasis mechanism of CONPs. As we all know, tumor angiogenesis, expression of matrix metalloproteinase，circulating tumor cells, and epithelial to mesenchymal transition (EMT) are all involved with the progression of tumor metastasis. In order to explore the mechanism of anti-metastasis effects, the subcutaneous melanoma and metastatic lung tumors mice models are built. After treated with CONPs, subcutaneous melanoma, metastases on the lung, and the circulating tumor cells, which are enriched and separated from peripheral blood by the single cell extraction system, are collected for further research. Single cell qRT-PCR, western blot and some other advanced methods are used to explore the influence of CONPs on the molecules expression, which are associated with tumor angiogenesis, expression of matrix metalloproteinase, and EMT regulatory network. Furthermore, in order to discover the key molecules in the upstream of EMT regulatory network and reveal the signaling pathway related with the metastasis inhibition, the normal transcriptome sequencing and single-cell transcriptome sequencing are performed. Finally, operation specimens of human melanoma will be collected to further validate the anti-metastasis effects of CONPs and the key signaling pathway associated with metastasis inhibition. In this research, we will reveal the effects of CONPs on the whole progression of melanoma metastasis and discover the significant signaling pathways associated with anti-metastasis pharmacological effects, providing meaningful example for new inorganic nanomedicine research and development, and pushing forward the mechanism study on the anti-tumor properties of CONPs.

英文关键词： melanoma;cuprous oxide nanopartilce;nanomedicine;tumor metastasis