Wnt信号通路在宫颈癌干细胞自我更新中的作用机制研究

Cancer stem cells (CSCs) are the main initiator for the development and progression of various cancers, and also the crucial carrier for cancer relapse, metastasis and drug resistance production. The self-renewal property, the most key property for the stem cells, is usually regulated by various signaling pathways, including Wnt, Notch and Hedgehog, et al. Therefore, it is becoming the new hot field that focus on the studies of the specific signaling transduction pathway of CSCs.Our previous studies have successfully isolated and identified the cancer stem cells from human cervical carcinomas; and found that LGR5 and SLUG expression affected the proliferation and tumor formation of cervical cancer cells through regulating the activities of the Wnt signaling pathway; and explored the role of the stem cell self-renewal related genes (OCT4,et.al) in the developement and progression of cervical cancer.In this project, we will try to elucidate: (1)the molecular mechanism of LGR5 in regulating the self-renewal property of cervical cancer stem cells through Wnt signal pathway; （2）the molecular mechanism of SLUG in regulating the self-renewal property of cervical cancer stem cells through Wnt signal pathway; (3)the relationship between the Wnt signal pathway and self-renewal related genes(OCT4,et.al)in the cevicval cancer stem cells; (4)the function analysis of the Wnt signaling pathway and its related molecules in cervical cancer stem cells,in order to explore the molecular mechanism underlying the Wnt signaling pathway in the regulation of the self-renewal of cervical cancer stem cells, and to establish the potential theory for the exploration of the new therapeutical technique targeting CSCs for cervical carcinomas.

肿瘤干细胞既是癌症发生发展的主要动因，又是癌症治疗三大难点-复发、转移和耐药性产生的关键载体。干细胞最关键的自我更新特性常常受到Wnt等信号通路的调控。因此，肿瘤干细胞自我更新信号传导通路的研究成为癌症研究的新热点。我们的前期研究已成功分离出人宫颈癌干细胞; 发现LGR5和SLUG通过调节Wnt信号通路影响宫颈癌细胞的增殖与肿瘤形成;解析了干细胞自我更新相关基因(OCT4等)在宫颈癌发生发展中的作用。本项目拟通过研究（1）LGR5通过Wnt通路调节宫颈癌干细胞自我更新的分子机制；（2）SLUG通过Wnt通路调节宫颈癌干细胞自我更新的分子机制；（3）宫颈癌干细胞中Wnt通路与自我更新相关基因（OCT4等）的关系；（4）宫颈癌干细胞中Wnt通路及其相关分子的功能分析，从而探讨Wnt信号通路对宫颈癌干细胞自我更新的调控机制，为靶向宫颈癌干细胞新治疗技术的开发奠定理论基础。

肿瘤干细胞既是癌症发生发展的主要动因，又是癌症治疗三大难点-复发、转移和耐药性产生的关键载体。干细胞最关键的自我更新特性常常受到 Wnt等信号通路的调控。因此，肿瘤干细胞自我更新信号传导通路的研究成为癌症研究的新热点。本项目通过研究LGR5通过 Wnt 信号转导通路调节宫颈癌干细胞自我更新的分子机制，探讨 Wnt 信号通路对宫颈癌干细胞自我更新的调控机制。我们的研究发现LGR5通过激活Wnt信号转导通路并上调Wnt信号转导通路中的关键分子β-catenin, c-myc和cyclin D1的表达可以促进宫颈癌细胞增殖及成瘤能力。通过体外肿瘤球形成实验、NOD/SCID小鼠成瘤实验、Transwell 小室等相关实验，证实LGR5通过激活Wnt信号转导通路可以上调干细胞相关标记物Nanog、Oct4、BMI1和ALDH蛋白的表达，从而增强宫颈癌细胞自我更新能力、体内致瘤能力、对顺铂的耐药性和细胞的迁移和侵袭。这些结果表明LGR5通过激活Wnt信号转导通路可以增强宫颈癌细胞自我更新能力并促进宫颈癌细胞增殖及成瘤能力。本课题通过研究LGR5基于Wnt信号转导通路调节宫颈癌细胞自我更新能力的调控机制，为靶向宫颈癌干细胞新治疗技术的开发提供理论基础。