miR181a/ZNF/PD-L1/ITGB4信号通路调控宫颈癌淋巴结转移机理研究

Lymph nodes metastasis is the most common metastatic way and plays significant role in the prognosis and treatment of cervical cancer patients.Therefore,illustration of its underlying mechanism and exploring new targets for treatment may be of great importance. In our previous research, we found miRNA181a could increase invasion and migration ability of cervical cancer cells via the induction of epithelial-mesenchymal transition (EMT). MiRNA181a may suppress the expression of zinc finger proteins (ZNFs) to increase the expression of programmed death 1 ligand 1(PD-L1), which may activate the integrin beta 4/FAK pathway to induce the EMT of cervical cancer cells, leading to lymph nodes metastasis. However, the specific relationship among the studies above and its mechanism remain unclear. Thus, we will perform dual-luciferase reporter experiment, chromatin immunoprecipitation (ChIP), gene chip, tissue array and image techniques for mice to further study miR181a/ZNF/PD-L1/ITGB4 pathway in vivo and in vitro, especially its function in lymph nodes metastasis and the inner network. This study will be of great theoretical significance and application value to elucidate the mechanism of lymph nodes metastasis, which can be used as molecular targets for the treatment of cervical cancer.

淋巴结转移是宫颈癌最常见的转移途径以及影响患者预后和治疗的重要因素，故揭示其机制并探寻新的治疗靶点是其有效治疗的关键。本项目前期研究发现miRNA181a可促进宫颈癌上皮间质转化(EMT)，增强细胞转移侵袭能力。随后研究发现miRNA181a可能通过抑制锌指蛋白（ZNFs）表达来增强程序性死亡分子配体1（PD-L1）表达，而PD-L1可激活整合素蛋白β4/FAK信号通路j进而促进宫颈癌EMT以及淋巴结转移过程。但这两者之间的联系以及具体作用机制尚不明确。因此，本项目拟在前期工作的基础上利用双荧光素报告基因、染色质免疫沉淀、基因/组织芯片以及小动物活体成像等体内外实验来研究miR181a/ZNF/PD-L1/ITGB4信号通路的内在调控网络及其促进宫颈癌淋巴结转移的作用机制，这对于明确宫颈癌淋巴结转移机理和寻找可用于转移风险评估和治疗的分子靶点具有重理论意义和潜在应用价值。

宫颈癌是一种女性生殖系统恶性肿瘤,组织学上以鳞状细胞癌常见。在其发病的早期,患者就可出现淋巴结的转移。宫颈癌淋巴结转移患者预后不良,更容易出现疾病的复发以及疾病相关的死亡。前临床对宫颈癌早期患者的治疗以手术为主,中晚期患者以放疗为主。目前,对宫颈癌淋巴结转移的分子机制仍然不明确,在淋巴结转移患者的治疗中缺乏有效的靶向治疗。因此阐明宫颈癌患者淋巴结转移机制的研究具有重要的理论意义与临床价值。程序性死亡配体1(Programmed death ligand1,pd-l1,)在肿瘤细胞以及浸润淋巴细胞中高表达,异常升高的PD-L1可抑制免疫监视以利于肿瘤细胞的转移,尤其是淋巴结转移。在我们前期研究中发现在早期可手术宫颈鳞癌患者中:淋巴结转移患者中宫颈肿瘤PD-L1阳性表达较无淋巴结转移患者阳性率高。本课题使用高通量筛选的方式初步分析了PD-L1在宫颈癌中的非免疫功能,然后重点研究了PD-L1调节宫颈癌细胞侵袭、转移以及瓦伯格效应的机制,相关研究结果将不仅为宫颈癌淋巴结转移分子机制提供理论基础,也为今后宫颈癌转移淋巴结的靶向治疗提供理论参考。