ZCRB1调节环状RNA HEATR5B编码881aa调控胶质瘤细胞有氧糖酵解的分子机制

The exploration for mediation of glioma cells aerobic glycolysis has become critical in revealing the mechanisms of glioma progression. Previous experiments have found ZCRB1 was lowly expressed in glioma cells and its level was negatively correlated with JMJD5 expression. Binding of ZCRB1 and circHEATR5B flanking sequences was discovered via circRNAs array screening. CircHEATR5B might encode a protein which termed 881aa. 881aa might modulate the activities of PKM2 and HIF-1α via repressing JMJD5. ZCRB1/circHEATR5B/881aa/JMJD5 axis regulates glioma cells aerobic glycolysis needs to be further investigated. This project aims to investigate the mechanisms of ZCRB1 accelerating the formation of circHEATR5B, circHEATR5B encodes 881aa, 881aa regulates glioma cells aerobic glycolysis via repressing JMJD5. By establishing xenograft models, we aim at revealing the mechanisms of 881aa, encoded via circHEATR5B, regulating glioma cells aerobic glycolysis and proliferation. This project will reveal novel mechanisms of glioma progression, and provide novel treatment targets for glioma cells metabolism.

介导胶质瘤细胞有氧糖酵解的研究对揭示胶质瘤的发生发展机制意义重大。前期发现胶质瘤细胞中ZCRB1低表达，与JMJD5表达负相关；通过芯片筛选等发现ZCRB1与circHEATR5B侧翼序列结合，circHEATR5B能编码881aa，881aa可能通过结合JMJD5调控PKM2、HIF-1α，进而调控胶质瘤细胞有氧糖酵解。ZCRB1/circHEATR5B/881aa/JMJD5途径调控胶质瘤细胞有氧糖酵解的机制有待验证。本项目拟研究ZCRB1促进circHEATR5B形成的机制；circHEATR5B编码881aa的机制；进一步研究881aa抑制JMJD5的表达在调控胶质瘤细胞有氧糖酵解中的作用机制；通过移植瘤模型，验证ZCRB1调节环状RNA HEATR5B编码881aa介导胶质瘤细胞有氧糖酵解的机制。本研究不仅能揭示胶质瘤发生发展的新机制，而且能为针对胶质瘤细胞代谢的治疗提供新靶点。

多形性胶质母细胞瘤 (Glioblastoma multiforme, GBM) 是发病率和致死率最高的原发性中枢神经系统恶性肿瘤，具有侵袭性生长、高复发率、预后差等特点。即使经过放化疗及手术治疗，患者的中位生存期仅为15个月。有氧糖酵解，又称Warburg效应，能够促进肿瘤的发生发展。PKM2 (pyruvate kinase M2) 是糖酵解过程的限速酶，在肿瘤细胞中主要以低活性的二聚体形式存在，在肿瘤有氧糖酵解中发挥着重要作用。ZCRB1 (Zinc finger CCHC-type and RNA-binding motif 1) 是由定位于染色体12q12的人ZCRB1基因编码的RNA结合蛋白。环状RNA是一类经反向剪接后，由3’末端和5’末端共价结合形成的环状非编码RNA，可作为microRNA海绵、蛋白骨架或编码蛋白参与肿瘤的发生发展。circHEATR5B (HEAT repeat containing 5B) 经检索发现可能编码一个881氨基酸的蛋白，被命名为HEATR5B-881aa。JMJD5 (Jumonji C domain-containing 5) 是组蛋白赖氨酸脱甲基酶家族成员，能够与PKM2直接作用，调控肿瘤细胞糖代谢。.本研究首先明确了ZCRB1、circHEATR5B、HEATR5B-881aa和JMJD5在GBM组织和细胞中的内源性表达水平以及对GBM细胞有氧糖酵解和增殖的影响，进一步探究上述因子之间的相互作用机制，以及调控GBM细胞有氧糖酵解和增殖的作用机制。本研究揭示了GBM细胞有氧糖酵解的新机制，为GBM的发病机制与治疗提供了新依据。.在此研究以外，研究组还发现了mmu_circ_0000296和miR-141-3p在调节慢性脑缺血诱导的鼠神经元凋亡的机制。