肝细胞内TCTP mRNA不同剪接本的异常分布可诱发肝细胞癌变的机制研究

Translationally controlled tumor proteinT（TCTP） is a cancer related protein which was found higher expresssion level inserveral cancers including hepacarcine. In cancer cell reversion, TCTP is the most remarkable biomarker. We found although protein level is increased in liver cancer tissue, the mRNA level is lower in cancer compare with para-tissue. One of TCTP mRNA isoforms （NM_001286272.1）may responsible for the phenomena. The isoforms of TCTP mRNA with different 3'UTR, a region responsible for expression regulation by binding with microRNAs. Our project try to find out the mechanisms of TCTP mRNA expression regulation and the factors involved in. Microarray assay will be taken to screen the microRNAs expressed differently in liver cancer tissue and normal tissue. The candidates will be analysed by bioinformatics method and verified by in vivo experiments. This research can help understanding the regulatory mechanism of TCTP expression.By thorough understanding of the mechanism will make a more precise strategy for drug design to TCTP.

肝细胞癌（HCC）是全球癌症相关死亡的第三大原因。翻译控制肿瘤蛋白（translationally controlled tumor protein，TCTP）是一种重要的癌症相关蛋白，高含量的TCTP蛋白是维持细胞癌症状态的重要biomarker之一。对比肝癌和癌旁组织，我们发现这一基因的mRNA和蛋白含量具有显著的不一致性。针对TCTP mRNA的不同剪接本检测发现，TCTP isoform1 （NM_001286272.1）可能与这一现象相关。具有相同编码区（CDS）和不同剪接本间的非编码区（UTR）剪接本的翻译效率差异提示着microRNA可能参与了调控。本课题拟在此基础上，深入研究剪接本特异性的翻译前调控机制，筛选可调节TCTP特定剪接本的microRNA。这一研究有助于肝癌诊断靶标的精确化，同时对于针对TCTP的药物设计和应用有指导意义。

明确了在肝脏细胞中TCTP基因的mRNA和蛋白之间存在负反馈自调控机制，且该机制在肝癌中被部分破坏。 TCTP蛋白可以抑制自身mRNA翻译，使已转录mRNA处于静息状态。mRNA表达量和蛋白水平处于内稳态平衡状态，从而保证了肝细胞的正常生理状态。而在肝细胞癌变过程中，这一平衡状态被打破，不受负反馈抑制调控的TCTP mRNA转录本开始大量表达，TCTP蛋白在细胞内累积，帮助癌细胞拮抗凋亡。TCTP基因的这一异常表达现象可以作为肝癌诊断的辅助biomarker，同时可以作为肝癌治疗的靶位点。我们的发现对于肝癌的临床诊断和治疗都具有重要意义。