CircRNA_0008255靶向作用miR-192-5p调控多发性骨髓瘤细胞自噬的分子机制及临床检验价值研究

多发性骨髓瘤（MM）研究中一个新兴的科学问题是：诱导激活的自噬成为保护恶性增殖的MM细胞存活的重要途径。环状RNA（circRNA）现被发现在调节自噬过程中作用关键，但其如何调控MM细胞自噬还知之甚少。我们前期研究中利用circRNA测序筛选出在MM中高表达的circRNA_0008255，且该circRNA定位于细胞质、并能特异激活MM细胞自噬，还可竞争性结合miR-192-5p，后者我们前期已证实能明确调节MM细胞自噬。因此，我们推测circRNA_0008255通过靶向作用miR-192-5p来调节MM细胞自噬；并拟通过自噬流监测、过表达或干扰及体内、外功能获得/缺失实验探讨circRNA_0008255/miR-192-5p轴调控MM细胞自噬的分子机制、评估circRNA_0008255对MM病情监测及预后判断的临床检测价值，为阐明上述科学问题、寻找MM潜在诊疗靶点提供思路借鉴。

Autophagy plays an important role in the pathophysiology of multiple myeloma (MM) . Of note, this requires a further investigation of regulatory mechanisms underlying the various stages of autophagy in MM cells. Several circular RNAs (circRNAs) are related to autophagy pathway in cancer cells. However, whether circRNAs participate in the regulation of autophagy in MM cells remains largely unknown. We performed a high-throughput RNA sequencing to detect the circRNA expression profiles in MM. We found that a novel circRNA, circRNA_0008255 was upregulated in newly diagnosed MM patients. Enforced expression of circRNA_0008255 could induce the autophagy in human myeloma cells and normal plasma cells. Furthermore, dual luciferase reporter assays showed that only miR-192-5p could directly bind the circRNA_0008255 sequence. Our previous studies have shown that miR-192-5p targets ATG2A to inhibit autophagy in human myeloma cells. Accordingly, we proposed that the circRNA_0008255-miR-192-5p axis could regulate the prosurvival autophagy in MM. To confirm this hypothesis, we will explore molecular mechanisms of circRNA_0008255-miR-192-5p axis and its regulation of the autophagic flux in MM cells in vivo and in vitro, by combination of various experiments, including RAN RIP，RNA pull down, luciferase report, inhibition and over-expression, animal experiments, and so on. Our aim is to provide a reference for further investigating the regulatory mechanisms underlying the various stages of autophagy in MM cells and finding a potential prognostic or therapeutic target for MM.