基于光学成像技术在体监测miR-200c在乳腺癌上皮间质转化过程中作用的研究

Breast cancer has become the first leading cause of cancer-related deaths amongst women. As metastasis is the major cause of breast cancer-related deaths, it is difficult to achieve early monitoring metastasis of breast cancer in vivo. Optical molecular imaging combines imaging with molecular biology, providing a new technical method to solve this problem. It uses optical imaging devices to detecting the signals of bioluminescence or fluorescence, for continuous, noninvasive monitoring in vivo. However, there is yet no specific targeting probe for epithelial-mesenchymal transition of breast cancer imaging. Based on previous studies and extensive literatures reading, we had found miR-200c was involved in EMT of breast cancer, and associated with metastasis of tumors. Our project intends to use optical molecular imaging to construct reporter gene system to monitor the activity of miR-200c, and validates its specificity and targeting ability of miR-200c in vitro and in vivo. Further, we will establish small animal reporter system and observe the consistency of the reporter system with EMT process of breast cancer. This study was designed to provide a theoretical basis for early monitoring EMT of breast cancer, and provide a new strategy and method for the ear diagnosis for EMT of breast cancer.

乳腺癌已成为现代女性健康的第一大杀手，患者因癌死亡的主要原因是肿瘤转移，现阶段尚未有早期在体监测乳腺癌转移的有效手段。光学分子成像技术将影像学与分子生物学相结合，为解决这一难题提供了新的技术手段，该技术利用光学成像设备检测生物发光及荧光发光信号，可连续、无创性进行活体监测，但目前尚缺乏特异性的靶向探针。在前期工作及深入文献分析的基础上，我们发现miR-200c参与了肿瘤细胞的上皮间质转化（EMT）过程，并与肿瘤转移过程密切相关。本项目拟利用光学分子成像方法构建监测miR-200c的表达和活性的双荧光素酶报告基因系统，并对其进行体内外鉴定，验证该系统的特异性和靶向性；构建小动物活体成像报告体系，观察该报告体系与乳腺癌EMT过程变化的一致性。本研究旨在为miR-200c作为乳腺癌药物的潜在治疗作用和光学分子成像技术在乳腺癌EMT的诊断提供理论依据，为乳腺癌EMT早期诊断提供新策略与新方法。

乳腺癌患者因癌死亡的主要原因是肿瘤细胞的转移，然而现阶段尚未有早期在体监测乳腺癌转移的有效手段。本项目利用光学分子成像技术可以连续、无创在活体进行检测的特点，结合生物信息学和分子生物学的方法和技术，设计并成功构建了可以在体监测乳腺癌上皮间质转化分子标志物miR-200c的光学分子报告基因系统，并通过体内外实验验证该报告基因系统可以实时、反复、非侵袭性地监测miR-200c的表达水平，该报告基因系统可受转化生长因子TGF-β1的调控，通过检测荧光素酶的活性来反映体内外miR-200c的表达量。本项目还进一步探讨了细胞间质重要组分COL1A1分子在乳腺癌细胞侵袭和转移的影响，发现在敲减COL1A1表达的乳腺癌细胞中，其划痕修复能力和侵袭转移能力均显著降低，提示COL1A1是抑制乳腺癌转移的潜在靶分子。综合上述结果，本项目为以乳腺癌上皮间质转化为靶点的抗肿瘤药物的研发提供了高通量的平台，同时也为进一步阐明乳腺癌侵袭和转移的机制提供了理论基础和实验依据。在本项目的资助下，在国内外杂志上发表论文15篇，其中SCI收录6篇，北大核心收录3篇，科技核心收录2篇；申请国家专利1项；获广东省科技进步奖三等奖1项。