精氨酸甲基转移酶PRMT7在多发性骨髓瘤浸润和转移过程中的作用机制研究

Multiple myeloma (MM) accounts for about 10% of hematological malignancy happened in middle-aged and elderly people，which is hard to cure. Molecular elucidation of multiple myeloma contributes to find new therapeutic target of MM. Research shows that epigenetic dysregulation plays an important role in the pathogenesis of MM, but it’s mechanism of action is currently unclear. It has been reported that the promoter hypermethylation of E-cadherin occur in MM patients, and our studies show that E-cadherin down-regulation enhances the invasive abilities of MM cell line, which imply that epigenetic modification of E-cadherin play a vital role in the development of MM. Our studies have demonstrated that PRMT7 is highly expressed in multiple MM cell lines and can repress transcription of E-cadherin gene. Furthermore, overexpression of PRMT7 prominently enhances the invasive capabilities of MM cells. MM cell lines, MM patient specimens and tumor model mice will be used in this study, we intend to clarify whether PRMT7 participate in the invasion, metastasis and progression of MM by epigenetic regulation of E-cadherin via in-vitro and in-vivo studies. This research finished on schedule will help to deeply understand the essence of MM disease and provide potential novel therapeutic target for multiple myeloma.

多发性骨髓瘤（MM）约占血液系统肿瘤的10%，多发于中老年人，至今仍难以治愈。深入探索MM发生的分子机制，有助于寻找MM新的诊治靶点。研究显示表观遗传调控异常在MM发病中起重要作用，然而其失调机制尚不清楚。已有研究表明MM患者体内E-cadherin启动子区高甲基化，我们的研究显示E-cadherin下调增强MM细胞的侵袭能力，这提示E-cadherin的表观遗传调控异常在MM发生过程中发挥重要作用。本研究已证实精氨酸甲基转移酶PRMT7在多种MM细胞中高表达并抑制E-cadherin的转录。过表达PRMT7能增强MM细胞的侵袭能力。本研究拟采用MM细胞系，MM患者样本和SCID小鼠肿瘤模型，通过体外和体内实验阐明PRMT7是否通过表观遗传调控E-cadherin的转录参与MM的浸润、转移和发生发展。本项目如期完成，将有助于加深对MM发病本质的认识，有望为MM的治疗提供潜在的新靶点。

表观遗传调控异常与MM的发生发展密切相关，我们前期研究提示E-cadherin下调与MM的发生发展关系紧密，但其下调的机制尚未见报道。同时，我们发现精氨酸甲基转移酶PRMT7可以抑制E-cadherin的转录进而影响MM细胞的生物学行为。而PRMT7作为表观修饰酶，其发挥作用可能需要partner蛋白的参与，我们利用蛋白质组学分析发现一个PRMT7新结合蛋白WDR5且二者表达呈正相关。通过进一步统计分析PRMT7与临床病人MM恶性程度的相关性，揭示PRMT7与MM患者耐药和生存率之间的关系，将有助于提供新的MM治疗策略。本研究初步阐明了PRMT7可能通过招募支架蛋白WDR5参与对E-cadherin的表观遗传修饰进而调控MM发生发展。另外，根据PRMT7酶活区域通过分子对接和高通量虚拟筛选获得多个靶向PRMT7的小分子化合物，这也为临床上恶性肿瘤的靶向治疗提供理论与实验依据。