EGFL6在脑膜瘤进展和恶变过程中的机制和作用研究

Meningioma is the secondary common intracranial tumor with nearly 10% malignant plus atypical subtypes, for which the molecular pathogenic and malignancy mechanism has not been fully clarified, and is still calling for effective drugs and comprehensive treatment. Our previous studies have established that ①EGFL6 expression was significantly elevated in both tumor tissues and serum of patients with meningiomas, and there were big differences between benign and malignant meningiomas; ②In vitro studies demonstrated that EGFL6-mediated PI3K/Akt signaling pathway could accelerate proliferation of meningioma cells. Based on these observations, it was suggested that EGFL6 not only may play an important role in the tumor progression and malignancy of meningiomas, in which both PI3K/Akt and EGFR signaling pathways might be the major modulating ways. So we are eager for the grant from NSFC and will carry out researches as followed: To further clarify the roles and mechanisms of EGFL6 in the progression and malignancy of meningioma via PI3K/Akt and EGFR signaling pathways and entry into nucleus to act as a transcriptional factor on both cellular and animal levels. The goals of our project are to discover novel mechanisms underlying the progression and malignancy of meningioma and to search for a breakthrough point on treating meningioma as a fairly common disease.

脑膜瘤是仅次于胶质瘤的颅内第二大发病率的肿瘤，其中近10%属于恶性或不典型，其发病和恶变机制尚未完全阐明，也缺乏有效的药物治疗。课题组前期研究发现：①EGFL6在脑膜瘤肿瘤组织中的表达水平及病人血清含量特异性地显著升高，而且在良恶性脑膜瘤之间存在明显表达差异；②原代培养的脑膜瘤细胞增殖与EGFL6浓度呈正相关，且与PI3K/Akt通路调控有关。因此EGFL可能与脑膜瘤的进展和恶变有关，PI3K/Akt以及EGFR通路可能是主要的调控途径。我们将深入开展：①利用脑膜瘤原代培养细胞，进一步明确EGFL和其介导的信号通路在脑膜瘤进展和恶变过程中的机制和作用；②在动物模型水平，进一步明确EGFL6及其介导的信号通路在体内对脑膜瘤生长、迁移和侵袭等的影响。通过上述研究，期望阐明EGFL6在脑膜瘤的进展和恶变中的分子机制，寻找脑膜瘤治疗新的切入点，探索开发阻断肿瘤进展的新途径。

脑膜瘤为中枢神经系统发病率最高的肿瘤之一，其中约 20%为高级别脑膜瘤（WHO II 和 III级），具有侵袭性生长、手术切除困难、术后复发率高等特点，是临床上治疗的难点。本课题拟利用脑膜瘤原代培养细胞，进一步明确EGFL6和其介导的信号通路在脑膜瘤进展和恶变过程中的作用和机制，并尝试建立脑膜瘤异体移植裸鼠模型，评价体外干预对脑膜瘤生长、迁移和侵袭等的影响，以期寻找脑膜瘤治疗新的切入点，探索开发阻断肿瘤进展的新途径。按照已有研究目标进行，如使用Co-IP、ChIP-Seq、Western-Blot等手段研究EGFL6与EGFR的相互作用，虽未能明确证实两者的直接作用关系，但发现EGF-EGFR-AKT通路可促进肿瘤增殖，并对EGFR在良、恶性脑膜瘤中的表达水平和患者预后进行了系统评价，初步明确了EGFR在脑膜瘤生长过程中发挥作用的分子机制。此外，课题组研究过程中还发现KLF4 (Krüppel-like factor 4) 可能参与脑膜瘤的发生过程，且与肿瘤的恶性演进密切相关。通过构建KLF4慢病毒载体，在体外分离培养的原代恶性脑膜瘤细胞株和裸鼠异位移植模型中证实了KLF4对恶性脑膜瘤增殖、侵袭、克隆形成及凋亡的影响，并对KLF4 - ERα-p53信号轴在高级别脑膜瘤中的调控作用做了初步的探索。