Pak4通过介导ERa靶向治疗I型子宫内膜癌的机制

According to its relatively slow progression on effective therapy and fast growing number of young women among incidence population, thus we are calling for a new treatment on Type I endometrial cancer.The molecular targeted therapy has been little progressed so far, which is mainly due to the lack of study with the breadth and depth on specific target molecules. As is known to all, estrogen, as one of the most important pathogenic factors of type I endometrial cancer, plays a role by binding to its receptor. The proliferative effect of protein kinase, Pak4 included, on endometrial cancer is most likely to have an association with ERα. We found the expression of Pak4 and ERα are co-regulated under the treatment of estrogen in pilot study, and further co-immunoprecipitation confirmed the Pak4 form complexes with ERα. Subject on the basis of preliminary results, we profile the expression of Pak4, Pak4ser474, ERα and ERαser118 on successfully established mice endometrial cancer model to prove their interaction. We also try to investigate the change of MAPK/PI3K signal transduction pathway under the interaction between Pak4 and ERα. We aim to prove that Pak4 influence both the biological behavior and therapeutic mechanism of endometrial cancer owing to its positive feedback with ERα. The study will provide a solid experimental basis for making Pak4 as a molecular target in cancer therapy.

I型子宫内膜癌（内膜癌）治疗效果的徘徊和年轻内膜癌病人的比例增加正在召唤新的治疗方法。迄今内膜癌分子靶向治疗进展甚微的主要原因是特异性靶分子研究的广度受限和深度受阻并存。如果雌激素是I型内膜癌重要致病因素且主要是通过其受体机制而起作用，那么包括Pak4在内的蛋白激酶对内膜癌的促增殖作用与ERα存在关联应是大概率事件。课题组预实验显示，雌激素作用下内膜癌细胞Pak4与ERα存在正性调控，免疫共沉淀证实了Pak4与ERα形成复合物。课题在预实验的基础上，应用已成功建立的小鼠内膜癌模型，检测模型中Pak4、Pak4ser474、ERα、ERαser118的表达；验证体内Pak4与ERα相互调控作用；探讨Pak4与ERα间的调控对MAPK/PI3K信号传导机制的影响，旨在证实Pak4通过与ERα正性调控，从而影响内膜癌生物学行为的调控和疗病机制。研究将为Pak4分子靶向治疗提供坚实的实验依据。

子宫内膜癌是女性生殖系统最常见的恶性肿瘤。年轻内膜癌患者对保留生育功能的迫切需求和目前以孕激素为主的保守治疗耐药性之间的矛盾，对现有子宫内膜癌的治疗模式提出极大的挑战。迄今内膜癌分子靶向治疗进展甚微的主要原因是特异性靶分子研究的广度受限和深度受阻并存。如果雌激素是I型内膜癌重要致病因素且主要是通过其受体机制而起作用，那么包括Pak4在内的蛋白激酶对内膜癌的促增殖作用与ERα存在关联应是大概率事件。课题组预实验显示，雌激素作用下内膜癌细胞Pak4与ERα存在正性反馈调控。课题在预实验的基础上，建立了小鼠Ⅰ型子宫内膜癌研究相关动物模型；证实Pak4及p-Pak4在内膜癌组织中高表达，且与肿瘤分期分级等临床病理参数正相关；Pak4可以调控内膜癌细胞增殖、迁移、侵袭及体内成瘤能力； Pak4通过调控cyclin D1表达及细胞周期变化促进内膜癌细胞增殖；Pak4通过ERK1/2-MMP-2信号通路促进内膜癌细胞迁移及侵袭；雌激素可部分通过PI3K/AKT信号通路上调Pak4活性，并可上调Pak4蛋白表达；Pak4与ERα形成复合物，参与其基因转录调控。本研究的结果在理论上加深我们对对内膜癌复杂的性激素调控机制的理解，同时为临床前通过调控Pak4进而诱导体内ERα表达下调的分子靶向治疗提供坚实的实验依据。