piRNA-823通过调控自噬途径促进多发性骨髓瘤疾病进展的研究

目前多发性骨髓瘤（MM）仍难以治愈，探索其新的顽固性进展机制非常重要。piRNA是一种新型非编码小RNA，通过与PIWI蛋白特异性结合来自我扩增。piRNA特异性极强，在体细胞中不表达，近期被发现与肿瘤发生、预后不良关系密切而备受关注。我们今年在Leukemia上报道了piRNA-823在MM细胞中高表达，促进MM细胞增殖、抑制其凋亡，并与MM患者ISS分期呈正相关，提示piRNA-823可能是促进MM进展的新机制。自噬是近期发现的参与MM进展、耐药的重要途径，结合基因芯片的生物学信息分析结果和文献报道，推测piRNA-823调控MM异常的关键通路极有可能是自噬途径。因此，本课题拟从临床、细胞、小鼠三个水平，系统验证piRNA-823在促MM进展中的重要地位，同时研究它是否通过自噬途径发挥作用，并从PIWI蛋白着手试图找到调控piRNA的新方法，以期为MM疾病分层和治疗提供一个新的靶标。

Until now, multiple myeloma (MM) is an incurable disease. It is very important to explore a new mechanism of refractory disease progression of MM. piRNA is a newly-discovered small non-coding RNA, which can be self-amplified through specificly combining with PIWI protein. piRNA exhibits high tissue specificity which is not expressed in body cells. Recently, piRNA attracted much attention because it was found to be related with tumorigenesis and bad prognosis of malignancies. This year, we reported piRNA-823 was highly expressed in myeloma cells in leukemia journal. It was found to promote the proliferation and inhibit the apoptosis of myeloma cells. In addition, we found piRNA-823 level correlated positively with ISS stage of MM patients, which suggested piRNA-823 might be a new mechanism of MM progression. Autophagy is an important pathway which was newly found involved in MM progression and drug resistance. According to the results from pathway enrichment analysis of DNA microarray data and literature reviews, it can be inferred that autophagy pathway might be the critical pathway by which piRNA-823 modulated MM cell abnormality. Therefore, in this study, we endeavoured to systematically verify the important role of piRNA-823 in promoting MM progression by clinical, cell and mouse model experiments, and simultaneouly determine if piRNA-823 promoted MM progression by modulating autophagy pathway. In addition, we tried to find new methods to regulate piRNA-823 based on PIWI protein. Thus this study aims to provide a novel potential target for disease stratification and treatment of MM patients.