LncRNA MEG3/miR-125b/BMP4信号轴调控M2巨噬细胞极化介导骨髓瘤进展的作用机制

骨髓瘤(MM)与骨髓微环境中巨噬细胞相互作用影响MM增殖,骨髓M2巨噬细胞增加预示MM增殖进展,但M2极化的分子机制尚不明朗.前期研究发现MM患者及小鼠荷瘤组织中M2增加与LncRNA-MEG3及BMP4下调,miR-125b上调相关.体外瘤细胞与M2共培养时证实miR-125b可靶向抑制BMP4促进M2极化.据此提出LncRNAMEG3/miR-125b/BMP4信号轴调控M2极化介导MM进展.本项目拟通过临床标本,细胞共培养及动物模型,以qRT-PCR,细胞转染,基因敲减等方法,明确MM细胞低表达LncRNA-MEG3,高表达miR-125b,抑制BMP4促进M2极化介导MM进展;沉默或过表达MM细胞LncRNA-MEG3,作为miR-125b海绵调节BMP4表达,调控M2极化的分子机制.本项目有望从全基因组角度揭示MM患者M2极化的机制,为MM微环境的免疫治疗提供新的靶点和实验依据.

The interaction between myeloma (MM) and macrophages in the bone marrow microenvironment affects MM proliferation.The increase of bone marrow M2 macrophages indicates the progression and proliferation of MM, but the mechanism of M2 polarization is not yet clear. The previous study found that increased M2 in MM and tumor- loaded tissues of mice were associated with the down-regulated of MEG3 and BMP4 and the up-regulated of miR-125b. When tumor cells in vitro were co-cultured with M2 found that miR-125b targeting inhibited BMP4 further promotes M2 polarization. Based on this we put forward the assumption: LncRNA MEG3/miR-125b/BMP4 signaling axis can regulate M2 macrophage polarization and further mediates MM progession.Through clinical specimens, cell co-culture systems, and animal models, We will clarify the molecular mechanism which LncRNA MEG3 is low on expression and miR-125b is overexpressing in MM cells were inhibiting BMP4 leads to M2 polarization then mediates MM progession; Knockdown or overexpression of LncRNA MEG3 in MM cells as miR-125b sponge to regulate BMP4 expression further regulates M2 polarization. This project is expected to reveal the mechanism of M2 polarization in MM patients from a genome-wide perspective and provide new targets and experimental basis for immunotherapy of MM microenvironment.