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

Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth / E. Leone, E. Morelli, M.T. Di Martino, N. Amodio, U. Foresta, A. Gullà, M. Rossi, A. Neri, A. Giordano, N.C. Munshi, K.C. Anderson, P. Tagliaferri, P. Tassone. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 19:8(2013 Apr 15), pp. 2096-2106. [10.1158/1078-0432.CCR-12-3325]

Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth

A. Neri;
2013

Abstract

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
Settore MED/15 - Malattie del Sangue
15-apr-2013
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/217700
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