多梳家族蛋白CBX7缺失调控高级别脑膜瘤细胞有氧糖酵解的机制和意义

高级别脑膜瘤（WHOII级和III级）因具有恶性生物学特征，手术全切除困难，术后易复发等特点，一直是临床上治疗的难点之一。申请人前期发现：80%的高级别脑膜瘤存在22号染色体长臂（Chr22q）杂合性缺失，导致位于其上的CBX7基因共缺失从而表达下降；CBX7过表达抑制高级别脑膜瘤细胞增殖和成瘤；CBX7能结合有氧糖酵解关键酶乳酸脱氢酶LDHA启动子和抑制LDHA转录；CBX7抑制高级别脑膜瘤细胞的有氧糖酵解。大量文献已证实有氧糖酵解促进肿瘤细胞增殖、侵袭等。我们由此假设：CBX7缺失通过提高LDHA表达，促进高级别脑膜瘤细胞有氧糖酵解及其恶性特性。鉴于此，本项目拟利用高级别脑膜瘤细胞系、小鼠脑膜瘤原位模型，阐释CBX7调控LDHA在高级别脑膜瘤恶性进展中的意义、机制，从而从代谢的角度阐释高级别脑膜瘤形成的分子机制，并为高级别脑膜瘤的临床治疗提供新思路。

High-grade meningioma (WHO grade II and III) are always one of the most difficulties in clinical treatment because of their malignant characteristics, difficulty to achieve total resection and more prone to recurrence. We found that 80% of high-grade meningiomas had a loss of heterozygosity on chromosome 22 long arm (Chr22q), resulting in the co-deletion and reduced CBX7 expression. In addition, CBX7 overexpression inhibited the proliferation and tumorigenesis of malignant meningioma cells. CBX7 could bind to the promoter of lactate dehydrogenase LDHA, a key enzyme of aerobic glycolysis, and inhibit the transcription of LDHA. CBX7 inhibited the aerobic glycolysis of high-grade meningioma cells. A large number of literatures have confirmed that aerobic glycolysis can promote the proliferation and invasion of tumor cells. We hypothesized that CBX7 deletion promotes the aerobic glycolysis and malignant transformation of high-grade meningioma cells by increasing LDHA expression. Based on this, this project intends to use high-level meningioma cell line and in situ mouse meningioma model to explore the significance and mechanism of CBX7 regulating LDHA in the malignant progression of high-grade meningioma, so as to explain the molecular mechanism of high-level meningioma formation from the perspective of metabolism, and provide new ideas for the clinical treatment of high-grade meningiomas.