Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue les effets d'inhibiteurs du micro-ARN 21 sur la croissance des cellules de myélome multiple
Purpose: Deregulated expression of microRNAs (miRNAs) plays a role in the pathogenesis and progression of multiple myeloma (MM). Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of MM. Experimental design: Here, we investigated the in vitro and in vivo anti-MM activity of miR-21 inhibitors. Results: Either transient enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of patient MM or IL-6-dependent /independent MM cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 significantly increased proliferation of MM cells, demonstrating its tumor promoting potential in MM. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B and BTG2), together with functional impairment of both AKT and ERK signaling, were achieved by transfection of miR-21 inhibitors into MM cells. In vivo delivery of miR-21 inhibitors in SCID mice bearing human MM xenografts expressing miR-21 induced significant anti-tumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors. Conclusions: Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-MM activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease.