桂枝茯苓丸在抑制卵巢癌中与STAT3相关的分子调控机制解析

卵巢癌是死亡率最高的妇科恶性肿瘤，腹腔扩散是导致低生存率的主要原因。桂枝茯苓丸为治疗妇科“癥瘕”之专方，对卵巢癌有较好的临床疗效。目前，桂枝茯苓丸抑制卵巢癌的药理学研究尚不深入。申请人前期对敲除STAT3卵巢癌细胞进行生物学与多组学分析，证实STAT3对细胞迁移以及肿瘤微环境应答具有决定性作用。桂枝茯苓丸下调卵巢癌细胞的p-STAT3，与STAT3信号网络和细胞侵袭密切关联。因此，为了阐明桂枝茯苓丸在抑制卵巢癌转移中与STAT3相关的分子调控机制，本项目将利用STAT3差异表达细胞模型和间充质干细胞提供微环境交流信号，通过体外与体内研究结合转录组分析，明确STAT3在肿瘤微环境信号交流中调控细胞转移的关键分子，解析桂枝茯苓丸调控STAT3信号网络的分子机制，探索其干预微环境信号交流调控细胞迁移的机制。从现代药理机制方面深入探索桂枝茯苓丸“消癥”的科学内涵，推动其治疗卵巢癌的临床应用。

Ovarian cancer is the most lethal gynecological malignancy. Frequent peritoneal dissemination is the main cause of low survival rate. Guizhi-Fuling Wan is a herbal formula treating for gynecologic pelvic masses. It has been clinically used for treating ovarian cancer and shown good outcome. Nonetheless, the therapeutic mechanisms of GZFL for the treatment of ovarian cancer (OC) has not been fully delineated. We previously generated STAT3 KO OC cell lines. In vitro and in vivo studies, as well as multi-omic analysis reveals that STAT3 is critical in regulating cell adhesion and migration, and responding to tumor microenvironment signaling. Our preliminary data and network pharmacology analysis showed that GZFL suppress p-STAT3 expression in OC cells, and is enriched in STAT3 signaling network and cell metastasis pathways. Therefore, we hypnosis that GZFL inhibits OC metastasis through targeting STAT3 signaling network. In this grant, STAT3 KO cells and carcinoma-associated mesenchymal stem cells will be used to carry out a series of in vitro and in vivo experiments, as well as RNA-seq analysis. Our work will verify the key molecules of STAT3 in regulating OC metastasis in tumor microenvironment, investigate detailed mechanisms of GZFL in targeting STAT3 signaling network, and explore the mechanism of its effect on tumor metastasis in microenvironment cell crosstalk. Our proposed pharmacological mechanisms of “Guizhi-Fuling Wan” will provide new insight for its clinical use in treating OC.