Myeloma cell adhesion to bone marrow stromal cells confers drug resistance by microRNA-21 up-regulation

Abstract

The bone marrow microenvironment plays a role in myeloma cell proliferation and adhesion-mediated drug resistance. In this study, we investigated microRNA-21 (miR-21) expression changes in myeloma cells that adhered to bone marrow stromal cells (BMSCs). In addition, we studied the synergistic effect of miR-21 inhibition with dexamethasone (Dex), doxorubicin (Dox), or bortezomib (Bort) on myeloma cell survival. We found that up-regulation of miR-21 expression was partially driven by nuclear factor-κB (NF-κB) signaling via myeloma cell adhesion to BMSCs. We also confirmed that RhoB is a miR-21 regulation target gene. Moreover, miR-21 inhibition combined with cytotoxic drug Dex or Dox inhibited myeloma cell survival more effectively than either treatment alone. These results suggest that the regulatory mechanisms of miR-21 expression may be a promising target for fine-tuning anti-myeloma therapy.

The resistance mechanisms of proteasome inhibitor bortezomib

“…Study of Wang et al and Zang et al showed bone marrow stromal cells (BMSCs) regulate the drug sensitivity of myeloma cells through the inhibited expression of miRNA and IL-6 plays a pivotal role in the occurrence of drug resistance [42,43]. IGF-1 produced by plasma cells, as well as by the marrow microenvironment, is a critical mediator of a number of downstream effects that contribute to multiple myeloma pathobiology.…”

MicroRNAs: A Puzzling Tool in Cancer Diagnostics and Therapy

“…The reactivation of tumor suppressor miRNAs, such as miR-29b or miRNA-30-5p, in myeloma cells, has therapeutic effects (40,41). On the other hand, miR-21 has been demonstrated to have an oncogenic feature (42). We proved that inhibition of the miR-21 halts the progression of multiple myeloma (MM) (43).…”

Circulating miRNAs: Potential Biomarkers for Diagnosis and Prognosis Prediction of Hematological Malignancies

“…In addition, the increase of serum miR-142-5p, miR-660 and miR-29a in MM patients were also been validated, of which, miR-29a proved its potent role in discriminating MM sera from healthy controls [29]. Since miR-21 was found to be related with malignant characteristic including tumorigenesis, invasion, and apoptosis resistance, another report from Wang et al also revealed that circulating miR-21 expression level was significantly upregulated in patients with MM and involved in progression of MM [30].…”