S100A6负调控CacyBP/SIP参与子宫内膜异位症发生的机制研究

The adhesion-invasion-angiogenesis of endometrial stromal cells at ectopic sites is an important link in the pathogenesis of endometriosis(EMs), but its mechanism is not clear. We found that S100A6 could promote proliferation and migration of mesenchymal cells, while CacyBP/SIP inhibited their biological function, and immunological Co-precipitation suggested the interaction. In addition, the study shows that CacyBP/SIP is a member of Beta-catenin, which is the key pathogenic molecule of EMs.Therefore, we speculate that S100A6 may promote the ubiquitization degradation of beta-catenin to participate in EMs by negatively regulating CacyBP/SIP. In this project, the effect of the absence of S100A6 domain on CacyBP/SIP nuclear transposition and phosphorylation on the degradation of beta-catenin was studied by using in vitro culture and in vivo animal model. It will be helpful to elucidate the occurrence of EMs caused by the negative regulation of CacyBP/SIP to effect the ubiquitization degradation of beta-catenin, and lay a good theoretical and experimental foundation for the therapeutic targeting of EMs.

子宫内膜间质细胞在异位处完成粘附-侵袭-血管生成是子宫内膜异位症（EMs）发病的重要环节，但其机制尚不清楚。我们前期发现S100A6能促进EMs间质细胞增殖和迁移，而CacyBP/SIP则抑制其生物学功能，且免疫共沉淀提示两者发生相互作用。另外研究显示CacyBP/SIP是抑制β-catenin泛素化降解的成员，β-catenin是EMs关键致病分子。故我们推测S100A6可能通过负调控CacyBP/SIP，影响其对β-catenin的泛素化降解参与EMs的发生。本项目拟应用EMs间质细胞体外培养及在体动物模型，研究S100A6结构域缺失对CacyBP/SIP的影响，CacyBP/SIP核转位及磷酸化影响β-catenin泛素化降解功能。将有助于阐明S100A6如何负调控CacyBP/SIP致其影响β-catenin的泛素化降解致EMs的发生，为EMs靶向治疗奠定良好的理论与实验基础。

子宫内膜异位症(Endometriosis,EMs)是一种妇科常见病，严重影响女性的健康和生活质量。其发病机制众多，EMs 虽是一种良性疾病，但具有类似恶性肿瘤的局部组织浸润侵袭、种植生长及转移等生物学行为。在位子宫内膜是EMs发病中的决定性因素，EMs异位病灶形成的关键在于子宫内膜细胞在异位处需完成粘附-侵袭-血管生成过程。前期研究发现S100A6不能直接与β-catenin发生特异性结合，而能与CacyBP/SIP发生特异性结合。进一步研究发现， CacyBP/SIP在 EMs在位内膜间质细胞中表达降低，并抑制 EMs迁移及侵袭能力。通过本项目研究发现，在EMs中，Ca2+浓度变化影响CacyBP/SIP核转位的情况,CacyBP/SIP的磷酸化水平与β-catenin的表达水平呈负相关，CacyBP/SIP的磷酸化水平随细胞周期变化而改变，并且CacyBP/SIP可能通过其磷酸化的改变来调节其泛素连接酶的活性，从而调控β-catenin的表达。通过对CACYBP/SIP蛋白免疫共沉淀混合物进行了质谱鉴定，结合CacyBP/SIP可促进β-catenin的泛素化降解， 推测CacyBP/SIP可能不是直接参与其降解过程，可能有其他蛋白参与其中，找到了TRIM21蛋白。TRIM21蛋白是一种E3 泛素蛋白连接酶，通过实验对TRIM21和CacyBP的相互作用进行了验证，发现两者之间能发生直接相互作用，推测CacyBP/SIP通过TRIM21蛋白促进了β-catenin的泛素化降解，导致了EMs的发生发展，为 EMs 靶向治疗奠定良好的理论与实验基础。