HE4和膜联蛋白A2（ANXA2）相互作用对卵巢癌发生发展的影响

Human epididymis protein 4 (HE4) is one of the ovarian cancer markers with the highest sensitivity and specificity by far, but most of the current researches focus on its application on the diagnosis, follow-up and prognosis for ovarian cancer as a biomarker, its mechanism on malignant tumor is still unknown. Our recent studies found that: (1) mass spectrometry analysis found that HE4 can combine with a protein named annexin A2 (ANXA2) with known structure; (2) fucose glycosylation presents on the surface of HE4 protein; (3) HE4 can interact with S100, CD147 protein; (4) HE4 can affect the biological behaviors of ovarian cancer mediated by ANXA2; (5) gene chip study prompted that HE4 can influence the expression of a plurality of signal molecules such as MAPK, FAK, etc. In consideration of the other researchers' findings that ANXA2 can promote the development of malignant tumors by interacting with multiple proteins such as S100 family, CD147, P-gp, we speculate that HE4 is a receptor of ANXA2, and it may form a protein complex with ANXA2, S100 family, CD147 to mediate the biological behaviors of ovarian cancer, ANXA2 may act as a " bridge" role in the HE4-ANXA2- protein complexes, the influence mechanism of the combination of HE4 and ANXA2 on the biological behaviors of ovarian cancer is related with MAPK and FAK signal pathways . The glycosylation of HE4 can further influence on the above processes. This project intends to clarify the interaction of HE4 and ANXA2 and their influence and mechanism on the occurrence and development of ovarian cancer.

人附睾蛋白4（HE4）是目前敏感性及特异性最高的卵巢癌标志物，相关研究主要集中在其作为标志物对卵巢癌的诊断及预后评估等方面，机制研究极少且较粗浅。我们发现：1.膜联蛋白A2（ANXA2）可能为HE4的受体；2.HE4 与S100A10、CD147亦存在相互作用；3.HE4存在岩藻糖基化修饰；4.HE4影响卵巢癌生物学行为可能通过ANXA2介导；5.芯片结果：HE4 影响MAPK及FAK通路相关分子表达。结合其他研究结果（ANXA2与S100A10、CD147等相互作用促进恶性肿瘤进展）推测：HE4与ANXA2是配-受体关系，HE4与ANXA2、S100A10、CD147等形成蛋白复合体，ANXA2在其中起"桥梁"作用；HE4与ANXA2结合对卵巢癌生物学影响与MAPK及FAK通路相关；HE4糖基化影响上述过程。本项目拟进一步阐明HE4与ANXA2的相互作用及其对卵巢癌发生发展的影响及机制。

卵巢癌在妇科恶性肿瘤中病死率居首位，其发生、发展的机制一直是妇科肿瘤基础与临床研究探索的重点。人附睾蛋白4(HE4)是目前敏感性及特异性最高的卵巢癌标志物，相关研究主要集中在其作为标志物对卵巢癌的诊断及预后评估等方面，机制研究极少且较粗浅。本研究采用生物化学、免疫分子生物学等研究方法，探讨HE4和膜联蛋白A2(ANXA2)相互作用对卵巢癌发生发展及耐药的影响及机制，证明了HE4与ANXA2均存在岩藻糖基化修饰，岩藻糖基化修饰增强HE4通过ERK-MAPK通路促进卵巢癌恶性生物学行为的能力；明确了HE4-ANXA2为配体-受体关系及相互结合区域；证明了HE4可通过ANXA2作为“桥梁”连接S100家族、CD147、MMPs、P-gp等蛋白，与ANXA2-MMP2形成蛋白复合体、通过ANXA2调控MMP2促进卵巢癌细胞侵袭转移，通过PI3K信号通路促进卵巢癌细胞增殖以及通过ANXA2抑制hsa-miR-129-5p的表达，进而促进P-gp的表达介导卵巢癌细胞对阿霉素的耐药。除此之外，我们还研究了其他HE4结合蛋白及下游蛋白对卵巢癌发生发展的影响及机制。我们的研究为控制卵巢癌耐药、寻找卵巢癌治疗靶点提供实验依据。