Significance of a tumor microenvironment-mediated P65-miR-30a-5p-BCL2L11 amplification loop in multiple myeloma

Despite significant progress in the treatment of myeloma, multiple myeloma (MM) remains an incurable he-matological 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 regu-latory 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-KB signaling pathway in myeloma cells and the NF-KB 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 sug-gesting 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.

Automated summary

Despite progress in myeloma treatment, cell adhesion-mediated drug resistance (CAM-DR) remains a major challenge. This study identified a miRNA-mRNA regulatory network in myeloma cells adherent to bone marrow stromal cells (BMSCs). It was found that BMSCs upregulated miR-30a-5p and downregulated BCL2L11 in the myeloma cells, while activation of NF-KB signaling pathway played a role in the expression of miR-30a-5p. Inhibition of miR-30a-5p or upregulation of BCL2L11 promoted apoptosis of myeloma cells, suggesting the potential clinical significance of miR-30a-5p inhibitor and PLBCL2L11 plasmid in CAM-DR treatment.