HMGB1作为内源性竞争性RNA通过mTOR通路促进HCC发生的作用及机制研究

The competitive endogenous RNA hypothesis (ceRNAs) thinks that RNA transcriptions can communicate to each other by a new mechanism, which is compete the same microRNAs through microRNA response elements (MREs) and to regulate the expression of other RNA transcriptions. This illustrates that mRNA not only can encoding protein, but also have the function to trans-regulate the action of other mRNA. The expression and secretion of nuclear factor HMGB1 were confirmed to closely related to the occurrence and development of a wide variety of tumors. But at present, the researches on the roles of HMGB1 in inflammation and liver cancer all focus on the function of protein coding. There are no reports about HMGB1 acts as ceRNA. In our previous studies, we forecasted the ceRNA network which including HMGB1 by bioinformation analysis. After detecting the expression and analysis the correlation in the very early hepatocellular carcinoma samples, we found that HMGB1 was the possible ceRNA for RICTOR, the very important gene of mTOR pathway. Based on these, we want to study the roles of HMGB1 on mTOR pathway as a ceRNA for RICTOR in vivo and in vitro, and discuss the way of HMGB1 in influencing of HCC occurrence on the level of RNA. We hope that through this study, to deepen the understanding of the new roles of HMGB1 on cancer, and provide new targets for the early prevention, and early clinical treatment of liver cancer.

竞争性内源性RNA假说(ceRNAs)认为RNA转录本之间能够通过一种新的机制相互通讯，即通过与microRNA反应元件（MREs）竞争相同的microRNA从而调节其他RNA转录本的表达，这说明mRNA不仅可以编码蛋白，还具备反式调节其他mRNA的作用。核因子HMGB1的表达和分泌被证实与多种肿瘤的发生、发展密切相关，但是其在肝脏炎症以及肝癌中的作用研究目前全部聚焦在其蛋白编码功能上，尚无其作为ceRNA发挥功能的报道。前期，利用生物信息学方法，我们对包含HMGB1的ceRNA网络进行了预测，通过在极早期肝癌样本中进行表达检测及相关性分析，我们进一步发现HMGB1有可能是mTOR通路中重要分子RICTOR的ceRNA。在此基础上，本项目拟从体内、体外两方面研究HMGB1作为ceRNA从RNA水平影响肝癌发生的可能作用和机制, 深化对其促癌作用的认识，为临床早期预防、治疗肝癌提供新的靶标。

RNA转录本之间通过microRNA反应元件（MREs）竞争相同的microRNA从而调节其他转录本的表达，这种新的相互调节、通讯的形式被称为竞争性内源性RNA(ceRNAs)机制，这说明mRNA不仅可以编码蛋白，还具备反式调节其他mRNA的作用。核因子HMGB1的表达和分泌被证实与多种肿瘤的发生、发展密切相关，但是其在肝脏炎症以及肝癌中的作用研究目前全部聚焦在其蛋白编码功能上，尚无作为ceRNA发挥功能的报道。研究人员利用生物信息学方法，对包含HMGB1的ceRNA网络进行了预测，通过在极早期肝癌样本中进行表达检测及相关性分析，发现HMGB1可能是mTOR通路中重要分子RICTOR的ceRNA；通过构建肝脏特异性miR-429基因敲除小鼠模型以及DEN诱导肝癌动物模型，研究人员证实miR-429介导了HMGB1对RICTOR的ceRNA调控；HMGB1通过ceRNA机制调控RICTOR的表达，活化下游mTOR-AKT通路，抑制SIRT4的表达，并解除对谷氨酸脱氢酶GDH的抑制性作用，最终通过影响肝癌细胞的谷氨酰胺代谢从体内、体外两方面促进肝癌的自我更新、恶性增殖和肿瘤发生。该研究有望深化对HMGB1在RNA水平促肝癌作用的认识，为临床早期预防、早期治疗肝癌提供新的靶标。