肿瘤干细胞自我更新能力的表观遗传调控机制的研究

项目名称： 肿瘤干细胞自我更新能力的表观遗传调控机制的研究

项目编号： No.81472733

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： 王艳

作者单位： 天津医科大学

项目金额： 74万元

中文摘要： 肿瘤细胞获得干细胞特征的过程中，上皮-间质转化（EMT）过程起到了十分重要的生物学作用。EMT 过程使肿瘤细胞经过表观遗传重编程之后具备了自我更新能力并易产生放化疗抵抗。本项目旨在通过高通量的二维电泳，亲和层析， ChIP-Seq及RNA-Seq等实验方法基于生物信息学的贝叶斯因果分析模型寻肿瘤干细胞获得与维持自我更新能力的重编程过程中的关键通路与关键调控因子，以及其启动与维持的分子机制，特别是表观遗传学机制，并深入研究该调控因子的生理病理学意义。目前我们已建立了可靠细胞模型，利用二维电泳与亲和层析鉴定出一系列与肿瘤干细胞干性调控相关的表观遗传调控因子及其蛋白相互作用网络，如CRL4B/SUV39H1/DNMT3A复合体等。该研究有助于阐明肿瘤干细胞表观遗传重编程的分子机制，建立和完善肿瘤干细胞的表观遗传学研究的新的技术体系，并为恶性肿瘤的转移预警、诊断、治疗和药物筛选提供新思路

中文关键词： C21_乳腺肿瘤；肿瘤干细胞；上皮-间质转化；自我更新；表观遗传

英文摘要： The epithelial-to-mesenchymal transition (EMT) affects critical steps of morphogenesis and tumor metastasis by interconverting epithelial cell type into cells with mesenchymal attributes. EMT programs activated in carcinoma cell enable those cells to acquire cellular traits associated with high-grade malignancy. Certain epithelial cells that pass through an EMT reprogramming process acquire the self-renewing trait associated with cancer stem cells (CSCs), also termed tumor-initiating cells. However, the epigenetic reprogramming mechanisms of self-renewal are still poorly understood. In this study, we will search for the essential pathways and key regulators involved in acquisition and maintenance of cancer stem cell self-renewal by using unbiased, genome-wide high throughput approaches including two dimensional electrophoresis, affinity purification, ChIP-Sequencing and RNA-Sequencing techniques, trying to answer questions about overall patterns of epigenetic mechanism process of CSC. In our preliminary work, we have constructed a reliable and efficient CSC model cell line which is sensitive to EMT inducers such as TGFb1, identified several key epigenetic regulators through 2D electrophoresis for CSCs, and find CRL4B/SUV39H1/DNMT3A form functionally coordinated complex in promoting self-renewal and tumor malignancy. This research will not only elucidate the epigenetic mechanisms that drive and maintain CSC, but also yield promising therapeutic targets and strategies for the prevention of metastasis - the most common fatal consequence of tumorigenesis.

英文关键词： Breast cancer;Cancer Stem Cell;EMT;Self-renewal;Epigenetics