KLF4与ER相互作用在间变型脑膜瘤发病过程中的机制研究

Meningioma is one of the most common primary tumors of the central nervous system, which accounts for over 35% of the total. Among them, nearly 20% are high-grade meningiomas (WHO grade II and III), characterized by invasive growth, poor resectability and tendency to recurrences. So far, the molecular mechanism underlying meningioma recurrence, malignant transformation, especially for the development and progression of anaplastic (malignant) meningioma is still unknown. Our established studies have isolated and characterized tumor stem-like cells from patients with anaplastic meningiomas. We found that KLF4 was highly expressed in anaplastic meningioma stem-like cells than arachnoid tissue, glioma stem cells and neural stem cells. Functional study and xenograft model confirmed overexpression of KLF4 significantly inhibited tumor growth. In vitro study demonstrated that KLF4 can interact with estrogen receptor (ERα), which was significantly associated with meningioma patients’ outcome as an independent factor. Furthermore, KLF4-ERα-p53 signaling pathway may play a key role in meningioma, regulating tumor proliferation, invasion and apoptosis. We are attempted to get a further investigation to illustrate the role and underlying mechanism of KLF4 and ER interaction in anaplastic meningioma, and their function in meningioma progression and malignant transformation, aiming to find novel way of treatment and therapeutic targets for anaplastic meningioma.

脑膜瘤为中枢神经系统发病率最高的肿瘤之一，约占颅内原发肿瘤总数的35%，其中约20%为高级别脑膜瘤（WHO II 和 III级）。而目前对于脑膜瘤复发、恶变，尤其是间变（恶性）脑膜瘤发生、演进的分子机制尚不明确。课题组前期研究中：通过从间变脑膜瘤中分离、原代培养并鉴定出了间变脑膜瘤干细胞样细胞；并从细胞和组织学水平发现、验证KLF4表达水平明显高于其它对照；细胞功能及裸鼠成瘤实验证实，过表达KLF4可显著抑制肿瘤生长。体外研究发现，KLF4可与雌激素受体ERα结合，后者的阳性表达是脑膜瘤患者预后的独立影响因素；而脑膜瘤中可能存在KLF4-ERα-p53途径调控肿瘤增殖、侵袭和凋亡。课题组期望进一步研究，阐明KLF4和ER相互作用在间变脑膜瘤中的详细作用机制，以及其在脑膜瘤进展和恶变过程中的作用，并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。

脑膜瘤最常见、发病率最高的中枢神经系统 原发性肿瘤，其中近20%属于高级别脑膜瘤， 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:1雌激素受体（ER）与3级脑膜瘤的预后相关，且是3级脑膜瘤的唯一独立性预后因素;2KLF4在恶性间变型脑膜瘤中与肿瘤的增值相关，且KLF4与ER存在蛋白的相互作用关系，表明KLF4与ER的相互作用可能与脑膜瘤的恶性进展相关。课题组发现了：1. 长链非编码RNA ASLNC17519过表达可增强核转录因子KLF4的转录活性，而不依赖于直接结合 2. ASLNC17519可编码肽17519-03aa 3. 17519-03aa可与KLF4蛋白的泛素化结构域结合并抑制其泛素化 4. 17519-03a体内体外均可抑制脑膜瘤的增值，促进脑膜瘤的凋亡。通过对KLF4信号通路的研究，课题组发现了小分子多肽对KLF4信号轴的治疗作用。课题组同时还进行了进一步探索，初步研究了CBX7-CMYC-LDHA信号轴对脑膜瘤代谢途径的影响。