lncRNA介导的M2型丙酮酸激酶分子调控在肝癌能量代谢中的作用

Abnormal energy metabolism is one of the important features in hepatocellular carcinoma arising and developing. So, revealing the mechanism is useful for prevention and treatment of such tumors. Our previous study found that the abnormal expression of long non-coding RNA closely related to the occurrence of hepatocellular carcinoma. The lncRNA-AY927547 regulated by DNA methylation can specificly bind with M2 pyruvate kinase (PKM2) and was associated with abnormal proliferation and migration of hepatoma. Therefore，we intend to further clarify the epigenetic regulation of lncRNA-AY927547 in hepatoma development. In the project, the specific binding of lncRNA with PKM2 and involving in the regulation of cell proliferation of hepatoma should be firstly confirmed. Then, the effect of lncRNA on PKM2 tetramer forming and the detail construction sites will be analyzed to reveal the molecular mechanisms involved in tumor aerobic glycolysis. Finally, animal experiments will also be performed to evulate the the potential value of the lncRNA-AY927547 adjustment strategy in hepatoma energy metabolism.

肝癌的异常能量代谢是其发生、发展的重要特征，解析其发生机制将为防治该类肿瘤提供重要策略。本课题组前期研究发现，长链非编码RNA（lncRNA）的异常表达与肝细胞肝癌的发生关系密切。其中，受DNA甲基化调控的lncRNA-AY927547与肿瘤能量代谢中的关键酶M2型丙酮酸激酶（PKM2）能发生特异性结合并与肿瘤的异常增殖及迁移相关。因此拟进一步明确表观遗传学修饰分子lncRNA-AY927547在肝癌发生、发展中的作用。本项目中，拟首先确证lncRNA-AY927547与PKM2发生特异性结合并通过影响其活性参与对肝癌细胞增殖的调节；其次通过分析该lncRNA分子对PKM2四聚体形成的影响及作用方式进而揭示RNA参与肿瘤有氧糖酵解的分子机制；最后通过动物体内实验探讨以lncRNA-AY927547为介导的对肝癌能量代谢调节策略的潜在价值。

肝癌的异常能量代谢是其发生、发展的重要特征，解析其发生机制将为防治该类肿瘤提供重要策略。本课题组前期研究发现，长链非编码RNA（lncRNA）的异常表达与肝细胞肝癌的发生关系密切。本研究表明，lncRNA-AY927547在肝癌细胞系及肝癌组织中异常甲基化；在获得该长链非编码RNA全长分子后确认了该分子在细胞水平存在对肝癌的抑制作用。进一步研究表明，lncRNA参与调控 PKM2的活性。通过生物信息学预测分析了HBx转基因小鼠肝脏差异表达的lncRNAs启动子中的转录因子结合位点。 我们的研究结果表明Evi1（亲嗜性病毒整合位点1）是非编码RNA的调节网络中的关键转录因子（TF）。我们进一步研究了EVI1在体外和体内的生物学功能，发现它可以促进肝癌发生的细胞增殖。本研究为长链非编码RNA通过调节丙酮酸激酶PKM2 活性抑制肝癌细胞增殖及迁移提供了较为充分的实验依据。提出了lncRNA通过影响重要代谢酶参与肿瘤糖酵解调节的机制。提出了一种新的lncRNA调节的通路机制。