靶向调节SOX2信号通路在人非小细胞肺癌治疗中的研究

SOX2 is an important stem cell marker, whose abnormal expression can lead to various tumor geneses. In preliminary data, we found that the expression level of SOX2 was increased in human non small cell lung cancer, and silencing SOX2 could suppress the proliferation of tumor stem cell and promote tumor cell apoptosis, but the mechanism reminds unexplored. In this study, we plan to in-depth study in the following aspects: (1) confirm the mechanism and signal pathway that SOX2 promotes the proliferation of tumor stem cell; (2) determine the apoptosis signal pathway that SOX2 regulates, ensure the downstream molecules, and find new mechanism in apoptosis signal pathway; (3) regarding SOX2 as the therapy targeting site, design, synthesize and prepare the Legumain dependent nanoparticals, which target tumor cells and specificitily transmit the siRNA to silence SOX2. In this study, we will provide the new idea to determine the mechanism of tumorigenesis, and via the novel nanopartical transmission system, we can efficiently and specificly suppress the tumor growth.

作为干细胞的标识性基因之一，SOX2的异常表达可能是导致多种人类肿瘤发生发展的重要原因。我们的前期研究表明，SOX2在人非小细胞肺癌中高表达，沉默SOX2可以有效抑制肿瘤干细胞的增殖，并促进肿瘤细胞凋亡，但其具体机制并未阐明。在本研究中我们拟从以下方面进行深入研究：（1）明确SOX2促进肺癌干细胞增殖的具体机制，并阐明其信号通路；（2）深入探讨SOX2参与的凋亡信号通路，明确其下游分子，为凋亡通路确定新的分子机制；（3）以SOX2为治疗靶点，设计、合成并制备Legumain依赖的、靶向肿瘤细胞并特异性传递靶向沉默SOX2的纳米颗粒药物传递系统。上述研究将为明确肿瘤发生机理提供新的思路和方向，并通过我们的新型纳米颗粒药物传递系统，以期达到靶向、高效地抑制肿瘤生长的治疗目的。

本课题组在项目执行期间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）明确了SOX2在多种肺部肿瘤中具有较高的表达水平并调控非小细胞肺癌等多种人实体瘤发生发展；2）研究了SOX2对多种关键基因表达的影响，初步探索了SOX2在非小细胞肺癌中致癌基因信号转导网络中的作用；3）明确了在非小细胞肺癌中SOX2 可以通过MAP4K-Survivin 信号转导通路调节细胞凋亡；4）完善了海藻酸包被的壳聚糖纳米颗粒制备技术并研究了其包裹的Legumain DNA 疫苗抗小鼠乳腺癌的效果；5）已发表SCI论文3篇。