Mir-222-221 Induce Dexamethasone Resistance by Targeting BBC3/PUMA in Human Multiple Myeloma

Dexamethasone is a conventional drug that effectively induces multiple myeloma (MM) cell death at presentation and in relapsed patients and continues to be used against MM alone or in combination with the new therapeutic agents. However, still remain unclear the mechanism of Dexamethasone resistance in clinic. We now report new mechanisms of Dexamethasone resistance implicating microRNAs (miR). MicroRNAs are noncoding small RNAs (18–25nt) that play an important role in the regulation of gene expression. Recently our profiling study in MM1S and MM1R cells has shown that miR-222-221 are highly expressed in MM1R cells as compared with MM1S cells. Our further investigation showed that enforced expression of miR-222-221 could render cells resistant to Dexamethasone and that the resistance to this drug could be partially restored by ectopic expression of PUMA without 3'UTR region. The list of microRNAs regulators for PUMA (BBC3) 3'UTR region in targetscan website includes miR-221 and miR-222. We also found a negative relationship between miR-222-221 levels and therapeutic response in clinical samples by using Q-RT-PCR, IHC and ISH methods. So we propose that miR-222-221 could target PUMA to induce Dexamethasone resistance in MM. Ectopic expression of miR-222-221 in MM1S cells resulted in decreased expression of PUMA protein and mRNA, whereas knockdown expression of miR-222-221 could restore PUMA expression in MM1S cells. Notably, miR-222-221-transfected MM1S cells became resistance to Dexamethasone as compared to vector-treated cells. Further, the knockdown of miR-222-221 sensitizes the MM1R cells to Dexamethasone-induced cell growth arrest and apoptosis. These findings indicate that the miR-222-221 play a significant role in regulation of PUMA expression level and could be potential targets for restoring PUMA expression and response to Dexamethasone therapy in a subset of MM patients. We are currently investigating the role of miR-222-221 in Dexamethasone resistant in vivo using well established mouse xenograft models of MM.

No relevant conflicts of interest to declare.