Purpose: Deregulated expression of miRNAs plays a role in the pathogenesis and progression of multiple myeloma. Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of multiple myeloma. Experimental Design: Here, we investigated the in vitro and in vivo anti-multiple myeloma activity of miR-21 inhibitors. Results: Either transient-enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient multiple myeloma cells or interleukin-6-dependent/independent multiple myeloma cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of multiple myeloma cells, showing its tumor-promoting potential in multiple myeloma. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B, and BTG2), together with functional impairment of both AKT and extracellular signal-regulated kinase signaling, were achieved by transfection of miR-21 inhibitors into multiple myeloma cells. In vivo delivery of miR-21 inhibitors in severe combined immunodeficient mice bearing human multiple myeloma xenografts expressing miR-21induced significant antitumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors. Conclusion: Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-multiple myeloma activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease.
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|Titolo:||Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth|
|Citazione:||Leone, E., Morelli, E., Di Martino, M.T., Amodio, N., Foresta, U., Gullà, A., et al. (2013). Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth. CLINICAL CANCER RESEARCH, 19(8), 2096-2106.|
|Appare nelle tipologie:||1.1 Articolo in rivista|
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