基于MUC1介导miR124/PHF19/E-cad轴表观遗传失衡研究附苓方抑制卵巢癌转移的分子机制

我国是卵巢癌高发国家，卵巢癌极易转移，致死率高。基于E-cad基因启动子区的表观遗传学修饰是导致肿瘤转移的重要始动因素之一,其中miR124/PHF19/E-cad轴表观遗传失衡尤为关键。多年临床研究发现，晚期卵巢癌患者的证候核心是虚寒夹瘀，用温阳行血的附苓方联合铂类治疗卵巢癌可以提高化疗通过率，降低远处转移。根据预研结果，申请人推测附苓方可能通过靶向膜表面受体MUC1，恢复miR-124/PHF19/E-cad轴表观遗传平衡，进而调控E-Cad等转移相关基因的表达，最终抑制卵巢癌的侵袭转移。因此我们拟构建相关腺病毒转染的细胞，用双荧光素酶报告系统、焦磷酸测序、人源性肿瘤组织异种移植模型等技术，从细胞、动物及临床三个层面，深入揭示附苓方如何干预MUC1-miR124-PHF19-E-cad表观遗传通路来抑制卵巢癌转移的内在机制，为丰富发病机制及靶向治疗提供新思路，为临床应用奠定基础。

China has high incidence and mortality of ovarian cancer which is easy to metastasis. Epigenetic changes based on the promoter region of E-cadherin gene are the key factors leading to tumor metastasis. Among them, the epigenetic balance of miR124/PHF19/E-cad is particularly critical. .Our clinical studies for many years have found that the core syndromes of advanced ovarian cancer patients are deficiency-cold and blood stasis.Compound fuling granule can warm yang and promote blood circulation, and treating ovarian cancer with compound fuling granule combined with platinum can improve the pass rate of chemotherapy and reduce distant metastasis..Based on previous studies, we speculated that compound fuling granule might restore the epigenetic balance of miR124 /PHF19/E-cad by targeting the membrane surface receptor MUC1, thereby regulate the expression of transfer-related genes such as E-cadherin, and ultimately inhibit the invasion and metastasis of ovarian cancer..Therefore, we plan to construct relevant adenovirus-transfected cells, and use techniques such as dual luciferase reporting system, pyrosequencing, and patient-derived tumor xenograft model to reveal the intrinsic mechanism of how compound fuling gramule interferes with the epigenetic pathway of MUC1-miR124-PHF19-E-cad to inhibit ovarian cancer metastasis from three aspects of cell, animal and clinical verification.It provides new ideas for enriching the pathogenesis and targeted therapy for ovarian cancer and lays a deeper foundation for further clinical application.