SOX2对IL6R转录调控在肿瘤转移中作用的研究

Recent studies support the concept that cancer stem cells (CSCs) are the roots of tumor recurrence and metastasis. SOX2, which is one of the marker genes for embryonic stem cells and CSCs plays an important role in maintaining their unique stemness properties. The applicant has been engaged in research on tumor and CSCs for many years and devoted to the exploration of novel therapeutic targets and methods for tumor. Our previous work demonstrated predominate overexpression of SOX2 in various types of human solid tumors, including the breast cancer and disclosed that SOX2 contributes significantly to tumorigenesis, metastasis and anti-apoptosis property of tumor cells. Based on previous work, we plan to apply multiple biological technologies or methods, including ChIP-Seq, tumor-bearing animal models and bioluminescent to perform the following experiments: 1). to verify the transcriptional regulation effect of SOX2 on IL6R；2）to further elucidate its underlying mechanism; 3). to test the function of IL6R in mediating metastasis promotion effect of SOX2. This study will help us to explore more leading therapeutic methods for the treatment of cancers.

目前的研究普遍认为肿瘤干细胞（CSCs）是肿瘤复发与转移的根源，而作为胚胎与CSCs的标识性基因之一的SOX2在维持干细胞特性中发挥着重要的功能。申请者长期从事肿瘤及CSCs的研究，并积极的探讨新的肿瘤治疗靶点及治疗方法。我们前期的研究结果发现SOX2在人乳腺癌等多种实体瘤中大量表达，并显著地促进肿瘤的发生、转移及抗凋亡特性。本课题拟在前期研究工作的基础上，结合CHIP-seq结果及活体动物体内光学成像等技术，通过体外实验及荷瘤动物模型，完成以下研究：1）明确肿瘤细胞中 SOX2对IL6R的转录调控作用；2）探讨SOX2对IL6R的转录调控机理；3）验证IL6R信号在介导SOX2促肿瘤细胞转移中的作用。本研究将为探索更有效的肿瘤治疗方法提供前沿性理论探讨。

本课题组在四年的研究工作中按照既定的研究计划执行，较好的达到了预期目标，完成了以下工作：1）体外实验证明SOX2能够调节IL6R的表达，并且发现在人的乳腺癌组织芯片中，SOX2与IL6R表达水平呈正相关性； 2）CHIP及双荧光报告实验明确SOX2通过结合在IL6R基因启动子附近直接调控其表达；3）发现SOX2调控H3K27Me3的表达，降低其在IL6R基因启动子附近区域的结合，从而也通过表观调控的方式调控IL6R基因的表达；4）通过体内外实验证明IL6R在介导SOX2的促肿瘤细胞转移中发挥重要的作用；5）通过多种动物实验模型的建立，进一步证明阻断IL6R信号一方面调节肿瘤微环境，如抑制VEGF、MMP等基因的表达。更重要的是直接阻断了CSCs中SOX2促肿瘤转移的功能，进而抑制了肿瘤的转移；6）已发表论文7篇，其中SCI论文6篇，5篇影响因子大于5分；7）已培养硕士研究生4人及博士研究生6人毕业。