E3连接酶Pirh2在多发性骨髓瘤硼替佐米耐药中的作用及机制研究

多发性骨髓瘤（MM）是一种单克隆浆细胞异常增生的恶性肿瘤，蛋白酶体抑制剂硼替佐米是目前治疗MM的最有效药物之一，但仍存在原发耐药及继发耐药现象。已证实E3连接酶决定泛素-蛋白酶体途径蛋白质降解的特异性。Pirh2是新近发现的参与p53反馈调节的E3连接酶，我们的前期研究发现野生型p53MM细胞Pirh2表达水平高于p53突变型细胞，而Pirh2高表达的细胞对硼替佐米治疗更敏感，且难治性MM患者Pirh2表达降低，提示Pirh2可能在MM细胞对硼硼替佐米耐药中发挥作用。本项目拟从细胞、蛋白及基因水平着手，深入探讨Pirh2在MM细胞对硼替佐米耐药中的作用及其机制，通过蛋白质谱分析筛选其中起关键作用的底物蛋白，进一步阐明Pirh2与不同类型MM疗效及预后的关系，寻求是否可通过有效调节Pirh2与底物蛋白间的相互作用，为探索MM治疗的新靶点提供理论依据。

Multiple myeloma (MM) is a malignant tumor with abnormal proliferation of monoclonal plasma cell, proteasome inhibitor bortezomib is one of the most effective drugs in treatment of MM, but still with primary and secondary resistance. Ubiquitin ligase E3 primarily determine the substrate specificity of ubiquitin proteasome system. Pirh2 (p53 - induced RING - H2 protein) is a newly discovered E3 ubiquitin ligase that antagonises p53. Our previous study found that Pirh2 expression of MM cell with wild type p53 was higher than p53 mutant cells, MM cells with higher Pirh2 level were more sensitive to bortezomib and mRNA expression level of Pirh2 in refractory/recurrence patients with MM was lower than newly diagnosed patients suggesting Pirh2 may play a critical role in growth and resistance of MM cells. The project is aimed to clarify the functions and mechanism of Pirh2 in MM cell growth and resistance based on celluar, protein and gene level through the protein spectrum analysis for screening the key substrates.To further explore the relationship between Pirh2 and effect and prognosis of patients with MM for providing theoretical basis for new targets of MM.