Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation
Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation
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DOI：
10.1186/s12943-019-1011-5
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发表时间：
2019-04-13
期刊：
影响因子：
37.3
通讯作者：
Hu, Yu
中科院分区：
文献类型：
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作者：
Ai, Lisha;Mu, Shidai;Hu, Yu
背景资料：骨髓源性抑制细胞（MDSC）和癌症干细胞（CSC）是肿瘤微环境中的两种重要细胞组分，其可改变癌症表型并影响患者存活。方法：采用流式细胞术检测骨髓瘤患者骨髓粒细胞-MDSCs（G-MDSCs）的表达，并分析其与疾病分期及患者生存期的关系。通过RT-PCR、流式细胞术、western blot和球体形成分析来研究G-MDSCs、皮尔纳-823和DNA甲基化对MM中干细胞维持的影响。然后构建皮下肿瘤小鼠模型来分析MM细胞中G-MDSCs诱导和/或皮尔纳-823敲减后的肿瘤生长和血管生成。我们的临床数据集验证了MM患者中高G-MDSC水平与总生存率差之间的相关性。此外，我们首次表明G-MDSC增强了MM细胞中CSC核心基因的侧群、球体形成和表达。此外，机制研究表明，G-MDSC触发皮尔纳-823表达，然后促进DNA甲基化，增加MM细胞的致瘤潜力。结论：总之，这些数据建立了G-MDSCs、皮尔纳-823、DNA甲基化和CSC核心基因之间的细胞、分子和临床网络，提示了一种新的针对MM微环境中G-MDSCs和CSC的抗癌策略。
Background: Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood.Methods: The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells.Results: Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo.Conclusion: Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.