新型表皮生长因子受体异构体EGFRvA对卵巢癌生长增殖和侵袭转移的作用及分子机制研究

The epidermal growth factor (EGFR) is a well-known transmemebrane protein receptor which is widely expressed at cell surface in mammalians. It has been reported that dysregulation of EGFR is tightly associated with various human maligancies and EGFR is a validated cancer therapeutic target. While the EGFR inhibitors are useful for some cancer treatment in clinical trials, their therapeutic effects on ovarian cancer are limited up to now. Recently, we identified one new EGFR isoform, EGFRvA. Structurally, compared with wild-type EGFR, EGFRvA contains a substitution of amino acids at C-terminus. Interestingly, it was revealed that this EGFR isoform (EGFRvA) was expressed in several ovarian cancer cell lines and tissues. Moreover, its protein expression was positively correlated with the stages of ovarian cancer. Further experimental data showed that EGFRvA was able to significantly promote proliferation, migration and invasion of ovarian cancer cells in vitro. These results implied that EGFRvA was likely to play critical roles in ovarian cancer progression. Thus, the aim of this project is to investigate EGFRvA　biological functions in the proliferation and metastases of ovarian carcinoma and uncover the underlying mechanisms, thereby expanding the current understanding of EGFR and providing new strategies for EGFR-targeted therapy of ovarian cancer.

表皮生长因子受体（EGFR）是哺乳动物体内一类广泛存在于细胞表面的跨膜受体。研究发现EGFR的失调与人类多种恶性肿瘤有着紧密的联系，而它也被证实是一个有效的肿瘤治疗靶点。虽然EGFR抑制药物在某些肿瘤的临床治疗中显示出了良好的效果，但目前其在卵巢癌中的疗效却并不理想。最近，我们发现了一种全新的EGFR异构体，EGFRvA。在结构上，与野生型EGFR相比，它在羧基末端发生了一段氨基酸的替换。有趣的是，检测结果显示此异构体在多个卵巢癌细胞系及组织样本中均有表达，而且其蛋白表达量与卵巢癌分期具有显著的正相关性。进一步实验表明EGFRvA在体外能显著增强卵巢癌细胞的生长增殖和迁移侵袭。这些结果提示了EGFRvA可能对卵巢癌的发生发展具有重要的促进作用。因此，本项目旨在研究EGFRvA对卵巢癌生长增殖和侵袭转移的作用及分子机制，从而拓展对EGFR的已有认识并为卵巢癌的EGFR靶向治疗提供新的思路。

表皮生长因子受体（EGFR）是一种细胞表面跨膜受体，它的失调与人类多种恶性肿瘤相关。虽然EGFR被证实是一个有效的肿瘤治疗靶点，但目前其抑制剂对卵巢癌的治疗效果却并不理想。该项目以我们前期发现的一种新型EGFR异构体EGFRvA为切入点，对EGFRvA在卵巢癌中的生物学功能和作用方式进行了深入研究。首先，我们发现与EGFR相比，EGFRvA蛋白表达与卵巢癌的恶性程度呈现出更明显的正相关性，而与卵巢癌病人的预后呈现出更显著的负相关性。这提示了EGFRvA可能在卵巢癌发生发展中扮演了更为重要的角色。进一步研究表明相比于EGFR，EGFRvA能更显著地促进卵巢癌生长，并增加卵巢癌对卡铂的耐药性。机制研究证明EGFRvA的845酪氨酸位点磷酸化水平与EGFR相比明显升高，进而激活下游的STAT5b通路，从而促进了卵巢癌的发生发展。该研究揭示了EGFR新型变异体EGFRvA在卵巢癌中的重要功能，一方面为拓展EGFR的已有认识提供了理论依据，另一方面为卵巢癌的EGFR 靶向治疗提供了新的思路。