Wang Yuelong, Deng Jiaojiao, Guo Gang, Tong Aiping, Peng Xirui, Chen Haifeng, Xu Jianguo, Liu Yi, You Chao, Zhou Liangxue
West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People's Republic of China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China.
J Neurooncol. 2017 Jan;131(1):21-29. doi: 10.1007/s11060-016-2273-z. Epub 2016 Sep 17.
Annexin A2 (AnxA2) is a highly conserved Ca2-regulated membrane binding protein, which affects cell mobility and tumor progression. Adamantinomatous craniopharyngioma (AdaCP) are a kind of epithelial tumors of the sellar region with high tendency to recur. Robust biomarkers are required to predict tumor behavior and to establish follow-up individualized treatment approaches. In this study, we firstly compared four surgical AdaCP samples with normal brain by two-dimensional gel electrophoresis (2DE) proteomic analysis. Potential prognostic biomarkers were further validated in a large cohort of 65 AdaCPs by immunohistochemistry. The effects of AnxA2 on AdaCP cells proliferation and migration were analyzed in vitro with isolated primary AdaCP cells as well as SV40T-immortalized cells. Finally, the gefitinib sensitivity of AdaCPs with differentially expressed AnxA2 and the potential molecular mechanisms were examined by flow cytometric analysis, Real-time PCR and immunoblot assays. Proteomic analysis indicated that AnxA2 was the protein spot with the most elevated expression in AdaCP samples. Immunohistochemistry assays indicated the expression level of AnxA2 was significantly higher in recurrent AdaCPs compared with primary ones. Moreover, AnxA2 AdaCP cells exhibited enhanced proliferation and migration ability compared with AnxA2 AdaCP cells in vitro. Further, we show that AnxA2 AdaCP cells exhibited elevated expression of EGFR and downstream p-AKT (S308) and p-AKT (S473), and were more sensitive to tyrosine kinase inhibitor gefitinib. Our data suggest that AnxA2 may serve as a promising biomarker for AdaCP progression, recurrence and drug susceptibility. Our data support potential clinical implications for the follow-up treatment of AdaCP patients with high AnxA2 expression.
膜联蛋白A2（AnxA2）是一种高度保守的钙调节膜结合蛋白，它影响细胞迁移和肿瘤进展。成釉细胞瘤型颅咽管瘤（AdaCP）是一种鞍区上皮性肿瘤，具有较高的复发倾向。需要可靠的生物标志物来预测肿瘤行为并建立后续的个体化治疗方案。在本研究中，我们首先通过二维凝胶电泳（2DE）蛋白质组学分析比较了4个手术切除的AdaCP样本与正常脑组织。通过免疫组织化学在65例AdaCP的大样本队列中进一步验证潜在的预后生物标志物。使用分离的原代AdaCP细胞以及SV40T永生化细胞在体外分析AnxA2对AdaCP细胞增殖和迁移的影响。最后，通过流式细胞术分析、实时PCR和免疫印迹分析检测AnxA2表达差异的AdaCP对吉非替尼的敏感性及其潜在分子机制。蛋白质组学分析表明，AnxA2是AdaCP样本中表达升高最明显的蛋白点。免疫组织化学分析表明，复发的AdaCP中AnxA2的表达水平明显高于原发性AdaCP。此外，与AnxA2阴性的AdaCP细胞相比，AnxA2阳性的AdaCP细胞在体外表现出增强的增殖和迁移能力。进一步研究表明，AnxA2阳性的AdaCP细胞中表皮生长因子受体（EGFR）及其下游的p-AKT（S308）和p-AKT（S473）表达升高，并且对酪氨酸激酶抑制剂吉非替尼更敏感。我们的数据表明，AnxA2可能是AdaCP进展、复发和药物敏感性的一个有前景的生物标志物。我们的数据支持对AnxA2高表达的AdaCP患者进行后续治疗的潜在临床意义。
