Ectopic expression of BIRC5-targeting miR-101-3p overcomes bone marrow stroma-mediated drug resistance in multiple myeloma cells

BMC Cancer. 2019 Oct 21;19(1):975. doi: 10.1186/s12885-019-6151-x.


Background: Multiple myeloma (MM) cells gain protection against drugs through interaction with bone marrow stromal cells (BMSCs). This form of resistance largely accounts for resistance to therapy in MM patients which warrants further exploration to identify more potential therapeutic targets.

Methods: We performed miRNA/mRNA qPCR arrays and western blotting to analyze transcriptional and translational changes in MM cells co-cultured with BMSCs. Drug cytotoxicity and apoptosis in MMGFP-BMSC co-cultures were measured using fluorescence plate reader and flowcytometry, respectively. miRNA was overexpressed in MM cell lines using Lentiviral transduction, miRNA-3'UTR binding was examined using luciferase assay.

Results: We found that BMSCs downregulated miR-101-3p and upregulated survivin (BIRC5) in MM cells. Survivin was downregulated by miR-101-3p overexpression and found to be a direct target of miR-101-3p using 3'UTR luciferase assay. Overexpression of survivin increased viability of MM cells in the presence of anti-myeloma drugs, and miR-101-3p inhibition by anti-miR against miR-101-3p upregulated survivin. Furthermore, overexpression of miR-101-3p or silencing of survivin triggered apoptosis in MM cells and sensitized them to anti-myeloma drugs in the presence of BMSCs overcoming the stroma-induced drug resistance.

Conclusions: Our study demonstrates that BMSC-induced resistance to drugs is associated with survivin upregulation which is a direct target of miR-101-3p. This study also identifies miR-101-3p-survivin interaction as a druggable target involved in stroma-mediated drug resistance in MM and suggests it for developing more efficient therapeutic strategies.

Keywords: Apoptosis; Bone marrow stroma; Multi-drug resistance; Multiple myeloma; Survivin; miRNA.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Bortezomib / pharmacology
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Coculture Techniques
  • Drug Resistance, Neoplasm*
  • Ectopic Gene Expression / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Mesenchymal Stem Cells / metabolism*
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Survivin / genetics*
  • Transfection


  • 3' Untranslated Regions
  • Antineoplastic Agents
  • BIRC5 protein, human
  • MIRN101 microRNA, human
  • MicroRNAs
  • Survivin
  • Bortezomib