miR-133a通过NF-κB通路调控炎症反应对骨髓增殖性肿瘤发病机制的研究

There are growing evidences that myeloproliferative neoplasms (MPNs) may present as a human inflammation model for cancer development and miRNAs play a important role in regulation between inflammation and cancer. Our previous studies showed down expression of miR-133a in MPNs and its relations with elevated inflammatory cytokines levels and NF-κB pathway. Herein, it is hypothesized that miR-133a may interact with NF-κB pathway by targeting its downstream genes, and contribute to MPN pathogenesis. Accordingly, we plan to investigate the role of miR-133a in regulating proliferation, differentiation and apoptosis of MPN hematopoietic stem cells, and its interaction with NF-κB pathway by targeting its downstream genes on cellular level by in vitro culture of MPN CD34+ cells, over expression and knock-out of miR-133a in normal CD34+ cells, and constructing miR-133a-deficient mice model. This research will help revealing the role of miR-133a of regulating inflammation in the pathogenesis of myeloproliferative neoplasms and its association with diagnosis and prognosis, and providing a theoretical basis for the screening of new therapeutic targets.

骨髓增殖性肿瘤(MPNs)是一个典型的慢性炎症向肿瘤发生的疾病模型，而miRNAs在炎症和肿瘤间发挥重要调控作用。我们前期实验结果发现MPNs患者miR-133a表达下调，并与炎症因子表达上调及NF-κB信号通路相关，推测miR-133a可能调控靶基因通过NF-κB信号通路参与炎症反应促进MPNs发病。本项目拟在体外培养MPNs患者CD34+细胞和沉默/过表达miR-133a的正常CD34+细胞，在细胞水平探讨miR-133a及其下游靶基因通过NF-κB通路对造血干/祖细胞分化、增殖及凋亡的作用，明确其参与炎症反应对MPNs发病的影响，揭示其与诊断和预后的关联，为筛选治疗新靶点提供理论基础。

骨髓增殖性肿瘤(MPNs)是一个典型的慢性炎症向肿瘤发生的疾病模型，而miRNAs在炎症和肿瘤间发挥重要调控作用。我们前期实验结果发现MPNs患者miR-133a表达下调，并与炎症因子表达上调及NF-κB信号通路相关，推测miR-133a可能调控靶基因通过NF-κB信号通路参与炎症反应促进MPNs发病。本项目以miR-133a及骨髓基质细胞通过炎症通路调节MPN肿瘤干细胞的生长增殖作为突破点，研究发现促炎症因子使MPN炎症因子和炎症信号通路蛋白的表达上调，并促进细胞增殖，而促炎症因子的拮抗剂抑制炎症因子及炎症信号通路蛋白的表达，并抑制细胞增殖。进一步通过MPN肿瘤细胞和基质细胞的共培养结果发现，骨髓基质细胞可促进HEL细胞增殖及细胞周期进程，与骨髓基质细胞共培养后HEL细胞分泌的多种细胞因子包括IL-6明显升高，且骨髓基质细胞可激活HEL细胞STAT3通路，提示两者通过IL-6/STAT3通路参与炎症反应对MPNs发病的影响，研究揭示了其与诊断和预后的关联，为筛选新的治疗靶点提供理论基础。