TPR调控tRNA出核运输与蛋白质合成及其在肺癌发生发展中的作用机制和临床意义

tRNAs play a critical role in protein synthesis and cell growth, and dysregulation of tRNA expression is closely linked to tumorigenesis and development. Therefore, it is of great significance to study the mechanism of tRNA expression regulation. Using the live cell imaging system established by our team, we have discovered in yeast that TPR affects the nuclear export of tRNAs. Our further study has proved that TPR mediates the association of tRNA genes with nuclear pores, coordinates tRNA transcription and nuclear export, and thus regulates protein synthesis and cell growth. Our analysis of the TCGA data has revealed that the expression of TPR is specifically elevated in lung cancer tissues, which predicts poor prognosis in lung cancer patients. However, the role of TPR in the tumorigenesis and development of lung cancer remains unknown, and its clinical implication is unclear. This proposed study aims to validate whether TPR regulates tRNA nuclear export and protein synthesis in lung cancer cell lines and animal models by gene overexpression and knockdown techniques. Also, it will elucidate the molecular mechanism by which TPR regulates lung cancer cell growth, apoptosis, migration and invasion. Furthermore, we will use pathological samples to analyze the correlation between TPR expression and the tumorigenesis, staging, metastasis, recurrence and prognosis of lung cancer. Collectively, the results from this study will expand our knowledge in the pathogenesis of lung cancer, and provide a solid foundation for the establishment of TPR as a novel diagnostic marker and therapeutic target in lung cancer.

tRNA在蛋白质合成和细胞生长中起重要作用，其表达失调与肿瘤发生发展密切相关，研究其调控机制意义重大。我们前期用自创的活细胞成像系统，在酵母中发现TPR影响tRNA的出核运输。进一步研究证明，TPR介导tRNA基因与核孔结合，协调tRNA的转录表达和出核运输，从而调控蛋白质合成和细胞生长。我们分析TCGA数据发现，TPR在肺癌组织中特异性高表达，且与患者的不良预后相关，但TPR在肺癌发生发展中的作用机制和临床意义尚不清楚。本项目拟在肺癌细胞与动物模型中，运用基因过表达和基因沉默技术，验证TPR是否调控tRNA出核运输与蛋白质合成，明确其对肺癌细胞生长、凋亡、迁移和侵袭等的调控及分子机制。我们还将分析肺癌病理标本中TPR的表达，评估其与肺癌发生、分期、转移、复发、预后等的相关性，确定其临床意义。本项目旨在拓展对肺癌发病机制的认识，为确立TPR作为新型肺癌诊断标记和治疗靶点提供理论和实验依据。

肿瘤细胞的旺盛增殖需要大大提高蛋白质合成水平，而蛋白质合成水平依赖于氨酰化tRNA的稳定供应。tRNA从细胞核转运到细胞质是一个高度受控的过程，但tRNA出核运输的具体机制尚未完全阐明。在本课题中，我们利用活细胞成像技术，在模式生物出芽酵母中观察特定tRNA基因的新生转录本，确定核篮蛋白TPR是tRNA出核运输的调节因子。随后，我们发现TPR在肺癌组织中表达显著升高，并与患者的不良预后相关。与此一致，敲低TPR抑制tRNA出核、蛋白质合成、细胞生长和迁移。我们进一步的研究显示，mRNA核输出因子NXF1与tRNA结合并介导其从细胞核转运到细胞质。综上所述，我们的研究成果揭示了一个协同调控tRNA出核及真核细胞蛋白质合成的保守机制。