LncRNA-NEAT1/EZH2/miR-181b信号轴在前列腺癌细胞有氧糖酵解中的作用与分子机制研究

Abnormal glucose metabolism mode has become a new mechanism of prostate cancer (PCa) progression. However, it is unclear that the role and mechanism of non-coding RNA pathway in PCa glucose metabolism. In recent study, we found that long non-coding RNA-NEAT1 (NEAT1) was abnormally over-expressed in PCa tissues, which was a predictor of poor prognosis. NEAT1 promoted aerobic glycolysis of PCa cells and bound to EZH2 protein. Additionally, EZH2 promoted aerobic glycolysis of PCa cells through inhibiting miR-181b transcription by histone methylation. Therefore, we speculated that NEAT1 promoted aerobic glycolysis of PCa cells through EZH2 mediated miR-181b inhibition and indirect activation of its target gene. In this project, we will firstly explore the role and molecular mechanism of NEAT1/EZH2/miR-181b axis in biological behavior of PCa cells. Secondly, we will analyse the correlation between NEAT1/EZH2/miR-181b axis and clinical index of patients with PCa (pathological level，clinical stage, and prognosis, etc). The results will provide important theoretical basis in revealing the novel mechanism for PCa development and exploring new targets for biological treatment of PCa.

异常的糖代谢方式已成为前列腺癌恶性进展的新机制。但是，有关非编码RNA信号通路在前列腺癌细胞糖代谢中的作用和机制尚不清楚。我们前期研究发现：（1）长链非编码 RNA-NEAT1（NEAT1）在前列腺癌中异常高表达，预示不良预后；（2）NEAT1促进前列腺癌细胞有氧糖酵解；（3）NEAT1在前列腺癌细胞中与EZH2蛋白结合；（4）EZH2通过催化组蛋白甲基化抑制miR-181b转录，促进前列腺癌细胞有氧糖酵解。据此，我们提出假说：NEAT1通过EZH2的介导抑制miR-181b转录，间接激活下游靶基因，从而促进前列腺癌细胞有氧糖酵解。项目拟：（1）探索NEAT1/EZH2/miR-181b信号轴的内在分子机制及其对前列腺癌细胞生物学行为的影响；(2)分析该信号轴与前列腺癌临床特征（级别、分期、预后）的相关性。研究结果将为揭示前列腺癌进展新机制和寻找前列腺癌生物治疗新靶点提供重要的理论依据。

研究背景：异常的糖代谢方式已成为前列腺癌恶性进展的新机制。但是，有关非编码RNA信号通路在前列腺癌细胞糖代谢中的作用和机制尚不清楚。我们前期研究发现，长链非编码 RNA-NEAT1（NEAT1）在前列腺癌中异常高表达，预示不良预后。但是有关NEAT1在前列腺癌进展中的生物学作用和分子机制尚不清楚。.主要研究内容：1.通过临床样本检测和患者随访，分析NEAT1的表达与前列腺癌临床特征（级别、分期、预后）的相关性；2.通过细胞与分子实验，探索NEAT1下游信号通路的内在分子调控机制；3.探索NEAT1/EZH2/miR-181b信号轴对前列腺癌细胞生物学行为的影响。.重要结果：1. LncRNA-NEAT1基因的表达水平随着前列腺癌的恶性进展显著上升；2.抑制LncRNA-NEAT1的表达后，前列腺癌细胞的增殖能力、迁移能力及有氧糖酵解水平显著降低，细胞的早期凋亡明显增加；3.NEAT1与EZH2蛋白结合；4. EZH2通过催化组蛋白甲基化抑制miR-181b转录，促进前列腺癌细胞有氧糖酵解；5.miR-181b通过直接结合在糖酵解限速酶基因HK2信使RNA 的3’UTR区来负向调控HK2的表达。.科学意义：明确 lncRNA-NEAT1 通过 EZH2 的介导表观抑制 miR-181b 转录，从而促进前列腺癌细胞有氧糖酵解的分子机制；为现有前列腺癌恶性进展机制提供补充；为寻找前列腺癌生物治疗新靶点提供理论依据。