HE4是目前敏感性及特异性最高的新型卵巢癌标志物，可作为化疗耐药的预测因子，但其与卵巢癌耐药机制研究目前几乎空白。我们发现：1.HE4与ANXA2为互作蛋白，二者高表达促进化疗耐药；2. HE4及ANXA2的表达影响上皮间质转化（EMT）相关分子变化；3.细胞内Ca2+稳态失衡促进EMT发生，ANXA2与互作蛋白结合后发生空间构象改变，影响细胞内Ca2+的调节；HE4上调钙通道蛋白TRPC6的表达；4.HE4/ANXA2均存在岩藻糖基化修饰，糖基化修饰增强HE4的功能；5.HE4影响MAPK及TGF-β通路相关分子表达。推测：HE4与ANXA2结合，影响ANXA2空间构象，增加细胞内Ca2+浓度，激活信号通路，影响细胞EMT，促进化疗耐药，糖基化修饰增强上述作用。针对HE4与ANXA2结合位点的抗体能阻断该复合体对耐药的影响。本项目拟阐明HE4与ANXA2相互作用介导卵巢癌化疗耐药的机制。

HE4 is a novel ovarian cancer marker with highest sensitivity and specificity. Although it could be a candidate to predict chemoresistance of ovarian cancer, the mechanism mediated by HE4 is still poorly understood. Our previously researches discovered that: 1) HE4 could interact with Annexin A2 (ANXA2), and their high expression levels facilitate the chemoresistance; 2) The expression level of EMT-related molecules changed in accordance with the expression of HE4 and ANXA2; 3) Imbalance of intracellular calcium could promote EMT; Intracellular calcium could be regulated by the spatial conformation change of ANXA2 after interaction with other proteins; HE4 could influence the expression of calcium channel protein TRPC6; 4) Both of HE4 and ANXA2 exist modification of fucosylation, and the glycosylation strengthened the function of HE4; 5) HE4 could influence the expression of MAPK and TGF-βsignaling pathway. Our hypothesis: The interaction of HE4 and ANXA2 could influence the spatial conformation of ANXA2, resulting in the increasing of intracellular calcium, to activate signal pathways and promote EMT and chemoresistance, furthermore, these effects could be enhanced by fucosylation of HE4 and ANXA2. The antibody specific to the binding site could interrupt the contribution of the complex to chemoresistance. This project aims to elucidate the mechanisms of ovarian chemoresistance mediated by the interaction of HE4 and ANXA2.