癌相关成纤维细胞通过IL-6激活STAT3/Notch信号通路促进宫颈癌转移和放、化疗抵抗的机理研究

Cervical cancer severely impairs the reproductive ability and health of women. Although the early screening and surgical treatment have reduced the morbidity and mortality, around 30，000 women in China are died of cervical cancer each year due to high metastasis and radio/chemo-resistance for patients especially at middle to late stages. Therefore, it is a key to seek molecular targets associated with metastasis and radio/chemo-resistance to improve the efficacy of cervical cancer treatment. The preliminary results from our research team showed that the long term chronic infection of cervical tissue with high-risk HPV not only induces malignancy of epithelial cells, but also stimulates the senescence of cancer-associated fibroblasts (CAF) in tumor microenvironment. The senescent CAF may activate the STAT3/Notch signaling pathways in other normal fibroblasts (NF) and in epithelial cells through interleukin 6 to remodel the tumor environment, thereby to facilitate the metastasis and radio/chemo-resistance of cervical cancer. This project will focus on the study of tumor microenvironment, by using CAF, NF, and cervical epithelial cancer cell lines with or without high risk HPV-infection, to systematically study the mechanisms how IL-6 activates STAT3/Notch signaling pathway to promote the migration, invasion, EMT development of cervical cancer cells, as well as the proliferation and self-renew of cervical cancer stem cells.

宫颈癌严重危害妇女生殖和健康。尽管早期筛查和手术治疗降低了其发病率和死亡率，但对于中、晚期患者，因其高转移和对放、化疗抵抗，在我国每年仍有近3万余人死于宫颈癌。因此，寻找转移和放、化疗抵抗相关分子靶标是提高宫颈癌疗效的关键。本课题组的前期研究结果表明，高危型人乳头瘤病毒（包括HPV16和18）长期慢性感染不仅诱发了上皮细胞癌变，而且诱导了微环境中癌相关成纤维细胞（CAF）的衰老，衰老CAF可能通过白细胞介素6（IL-6）激活其他正常成纤维细胞（NF）和上皮细胞中STAT3/Notch信号，重建肿瘤微环境以促进宫颈癌转移和对放、化疗的抵抗。本课题拟以研究肿瘤微环境为主，用CAF和NF，以及高危和非高危型HPV感染的宫颈癌细胞系，从体外细胞和分子水平、体内动物和人体组织水平系统研究IL-6活化STAT3和Notch信号通路促进宫颈癌细胞迁移、侵袭、EMT发生以及癌干细胞分化与自我更新的作用机制

宫颈癌严重危害妇女生殖和健康。尽管早期筛查和手术治疗降低了其发病率和死亡率，但对于中、晚期患者，因其高转移和对放、化疗抵抗，在我国每年仍有近3万余人死于宫颈癌。因此，寻找转移和放、化疗抵抗相关分子靶标是提高宫颈癌疗效的关键。本课题组的前期发现高危型人乳头瘤病毒（包括HPV16和18）长期慢性感染不仅诱发了上皮细胞癌变，而且诱导了微环境中癌相关成纤维细胞（CAF）的衰老，衰老CAF可能通过白细胞介素6（IL-6）激活其他正常成纤维细胞（NF）和上皮细胞中STAT3/Notch信号，重建肿瘤微环境以促进宫颈癌转移和对放、化疗的抵抗。本课题研究发现肿瘤间质微环境中癌相关成纤维细胞（CAFs）可能通过其旁分泌的IL-6使宫颈癌上皮细胞STAT3激活和Snail 1上升，诱导EMT发生，从而促进宫颈癌的扩散和转移；IL-6通过促进STAT3和Notch3活化入核，增强宫颈癌细胞的放疗抵抗;进一步研究发现宫颈癌细胞可能主要通过与肿瘤微环境中IL-6及其受体，通过自分泌或旁分泌途径、并以IL-6/HPV E6/STAT3/Notch信号轴为主，促进肿瘤的生长与转移，并对放、化疗产生抵抗。