Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China.
School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
Exp Cell Res. 2022 Jun 1;415(1):113113. doi: 10.1016/j.yexcr.2022.113113. Epub 2022 Mar 23.
Despite significant progress in the treatment of myeloma, multiple myeloma (MM) remains an incurable hematological malignancy due to cell adhesion-mediated drug resistance (CAM-DR) phenotype. However, data on the molecular mechanisms underlying the CAM-DR remains scanty. Here, we identified a miRNA-mRNA regulatory network in myeloma cells that are directly adherent to bone marrow stromal cells (BMSCs). Our data showed that the BMSCs up-regulated miR-30a-5p and down-regulated BCL2L11 at both mRNA and protein level in the myeloma cells. Besides, luciferase reporter genes demonstrated direct interaction between miR-30a-5p and BCL2L11 gene. Moreover, the BMSCs activated NF-ΚB signaling pathway in myeloma cells and the NF-κB P65 was shown to directly bind the miR-30a-5p promoter region. Moreover, suppression of the miR-30a-5p or upregulation of the BCL2L11 promoted apoptosis of the myeloma cells independent of the BMSCs, thus suggesting clinical significance of miR-30a-5p inhibitor and PLBCL2L11 plasmid in CAM-DR. Together, our data demonstrated the role of P65-miR-30a-5p-BCL2L11 loop in CAM-DR myeloma cells. These findings give new insights into the role of tumor microenvironment in the treatment of patients with myeloma.
尽管骨髓瘤的治疗取得了重大进展，但多发性骨髓瘤（MM）仍然是一种无法治愈的血液恶性肿瘤，这是由于细胞黏附介导的药物耐药（CAM-DR）表型。然而，关于 CAM-DR 背后的分子机制的数据仍然很少。在这里，我们鉴定了骨髓瘤细胞与骨髓基质细胞（BMSCs）直接黏附时的 miRNA-mRNA 调控网络。我们的数据表明，BMSCs 在骨髓瘤细胞中同时在 mRNA 和蛋白水平上上调了 miR-30a-5p，并下调了 BCL2L11。此外，荧光素酶报告基因显示 miR-30a-5p 与 BCL2L11 基因之间存在直接相互作用。此外，BMSCs 激活了骨髓瘤细胞中的 NF-ΚB 信号通路，并且 NF-κB P65 被证明可以直接结合 miR-30a-5p 启动子区域。此外，抑制 miR-30a-5p 或上调 BCL2L11 可促进骨髓瘤细胞的凋亡，而与 BMSCs 无关，因此提示 miR-30a-5p 抑制剂和 PLBCL2L11 质粒在 CAM-DR 中的临床意义。总之，我们的数据证明了 P65-miR-30a-5p-BCL2L11 环在 CAM-DR 骨髓瘤细胞中的作用。这些发现为肿瘤微环境在骨髓瘤患者治疗中的作用提供了新的见解。
