核糖体蛋白S3亚基上调前列腺素内过氧化物合成酶2促进急性白血病发展及其机制研究

The abnormally high expression of prostaglandin endoperoxide synthase 2 (PTGS2) acute leukemia is often observed.However,the regulatory mechanism of PTGS2 expression and its function in acute leukemia is still unclear. Our previous studies found a new binding and regulating proteins to PTGS2 promoter, ribosomal protein S3 (RPS3), which is highly expressed in acute leukemia. Knocking down the expression of RPS3 in acute leukemia causes significant decrease in proliferation and increase in apoptosis of their cell.However, the molecular mechanism of RPS3 regulating PTGS2 and its function in acute leukemia is not known. In this study, we will investigate the molecular mechanism of how RPS3 regulate the promoter activity,gene expression and functional activity of PTGS2 and their effect on biological functions such as cell proliferation and apoptosis and related signalling pathways,by gene overexpression and gene silencing in acute leukemia cell lines and animal models,which will help to determine whether RPS3 up-regulate the expression of PTGS2 and promote the growth of acute leukemia cells and tumor progression.In addition,we will analyze the correlation between RPS3/PTGS2 and MICM classifications and prognosis of acute leukemia together with their clinical data and evaluate their clinical significance and potential applications in the molecular diagnosis and prognostic prediction of acute leukemia.This study will provide a basis for RPS3/PTGS2 as a new therapeutic target for acute leukemia.

前列腺素内过氧化物合成酶2(PTGS2)在急性白血病中常异常高表达，但其具体作用与调控机制不清楚。前期我们发现一个新的PTGS2启动子结合与调控蛋白-核糖体蛋白S3亚基(RPS3)；且它在急性白血病中异常高表达；敲低其表达，可显著抑制细胞生长，诱导凋亡。但RPS3调控PTGS2的机制及其在急性白血病中的作用不清楚。本项目拟在急性白血病细胞与动物模型中，通过基因沉默及过表达技术，研究RPS3对PTGS2启动子活性、基因表达和功能活性的调控，以及对细胞增殖和凋亡等生物学功能及相关信号通路的影响，以明确RPS3靶向上调PTGS2表达促进急性白血病细胞生长和肿瘤进展。此外，我们将结合临床资料，分析RPS3/PTGS2与急性白血病MICM分型和预后等的相关性，评估它们在分子诊断和预后预测上的临床意义和应用价值。本项目可以为确立RPS3/PTGS2通路作为治疗急性白血病的新靶点提供依据。

急性白血病的预后仍不理想，迫切需要进一步研究其发生发展的分子机制。前列腺素内过氧化物合成酶2(PTGS2)在急性白血病中常异常高表达，但其具体作用与调控机制不清楚。前期我们发现一个新的PTGS2启动子结合与调控蛋白-核糖体蛋白S3亚基(RPS3)；且它在急性白血病中异常高表达；敲低其表达，可显著抑制细胞生长，诱导凋亡。但RPS3调控PTGS2的机制及其在急性白血病中的作用不清楚。本项目在急性白血病细胞与动物模型中，研究了RPS3对PTGS2启动子活性、基因表达和功能活性的调控，以及对细胞增殖和凋亡等生物学功能及相关信号通路的影响，明确了RPS3 通过靶向上调PTGS2表达促进急性白血病细胞生长和肿瘤进展。此外，我们分析了RPS3/PTGS2与急性白血病预后的相关性，发现RPS在分子诊断和预后预测上有重要价值。而且，我们在以上基础上进一步探索了上游分子调控机制，发现了circPVT1和miRNA-124-3p通过调控RPS3/PTGS2通路调控急性白血病发生发展的新机制。本项目可以为确立circPVT1-miRNA-124-3p-RPS3-PTGS2通路作为治疗急性白血病的新靶点提供依据。