人附睾蛋白4（HE4）是目前敏感性及特异性最高的卵巢癌标记物，近期发现其可作为化疗耐药的预测因子，但是HE4与卵巢癌耐药的作用机制仍知之甚少。申请者发现①HE4及其岩藻糖基化Lewis y抗原是卵巢癌耐药和不良预后的主要独立危险因子；②基因芯片分析提示膜联蛋白A8(ANXA8)与HE4的表达存在一致性且已初步证明二者蛋白存在相互作用；③基因分析同时提示HE4可影响MAPK信号通路。因此，申请者设想HE4可能通过与ANXA8相互作用促进MAPK信号通路激活而增强卵巢癌粘附介导的耐药，HE4的岩藻糖基化增加上述作用。本项目拟通过构建HE4及ANXA8增强及沉默表达的人卵巢癌粘附耐药细胞模型及裸鼠移植瘤模型，采用分子生物学、生物化学等方法，从分子、细胞、组织等水平多方面探讨HE4在卵巢癌粘附耐药中的重要作用及调控机制，为卵巢癌化疗耐药研究提供新思路。

Currently, human epididymis protein 4 (HE4) is the most sensitive and specific biomarker for ovarian cancer detection, recent studies have found that it is a prognosis factor for drug-resistance in ovarian cancer, however, the mechanism of HE4 on drug resistance in ovarian cancer is still is still poorly understood. The applicant found that: (1) both the HE4 and its fucosylated antigen Lewis y are independent risk factors for drug resistance and bad prognosis in ovarian cancer patients; (2) microarray analysis showed that the gene expression of Annexin A8 (ANXA8) is coordinated with that of HE4, and preliminary studies have proved the existence of interaction of these two proteins; (3) further gene enrichment analysis showed that HE4 may effect on the MAPK signaling pathway. Thus, the applicant assumed that HE4 may promote the adhesion-mediated drug resistance (CAM-DR) through the interaction with Annexin A8 by enhancing the activation of MAPK signal pathway in ovarian cancer, and the fucosylation modification may boost the above effect. This item designs to construct the human ovarian cancer adhesion drug resistance cell models and nude mice xenograft tumor models with HE4 or ANXA8 overexpressing or silence, by using of the methods of molecular biology, biochemistry, etc, to discuss the important roles and modulation mechanisms of HE4 in CAM-DR of ovarian cancer via multiple levels such as molecular, cellular and tissue, etc. Finally, to provide new ideas for drug resistance studies in ovarian cancer.