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

Emanuela Leone, Eugenio Morelli, Maria T. Di Martino, Nicola Amodio, Umberto Foresta, Annamaria Gullà, Marco Rossi, Antonino Neri, Antonio Giordano, Nikhil C. Munshi, Kenneth C. Anderson, Pierosandro Tagliaferri, Pierfrancesco Tassone

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2096-2106
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number8
DOIs
Publication statusPublished - Apr 15 2013

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Multiple Myeloma
Growth
MicroRNAs
Heterografts
Transfection
Up-Regulation
In Vitro Techniques
Lentivirus
SCID Mice
Extracellular Signal-Regulated MAP Kinases
Mesenchymal Stromal Cells
Human Activities
Interleukin-6
Research Design
Down-Regulation
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Leone, E., Morelli, E., Di Martino, M. T., Amodio, N., Foresta, U., Gullà, A., ... Tassone, P. (2013). Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth. Clinical Cancer Research, 19(8), 2096-2106. https://doi.org/10.1158/1078-0432.CCR-12-3325

Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth. / Leone, Emanuela; Morelli, Eugenio; Di Martino, Maria T.; Amodio, Nicola; Foresta, Umberto; Gullà, Annamaria; Rossi, Marco; Neri, Antonino; Giordano, Antonio; Munshi, Nikhil C.; Anderson, Kenneth C.; Tagliaferri, Pierosandro; Tassone, Pierfrancesco.

In: Clinical Cancer Research, Vol. 19, No. 8, 15.04.2013, p. 2096-2106.

Research output: Contribution to journalArticle

Leone, E, Morelli, E, Di Martino, MT, Amodio, N, Foresta, U, Gullà, A, Rossi, M, Neri, A, Giordano, A, Munshi, NC, Anderson, KC, Tagliaferri, P & Tassone, P 2013, 'Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth', Clinical Cancer Research, vol. 19, no. 8, pp. 2096-2106. https://doi.org/10.1158/1078-0432.CCR-12-3325
Leone E, Morelli E, Di Martino MT, Amodio N, Foresta U, Gullà A et al. Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth. Clinical Cancer Research. 2013 Apr 15;19(8):2096-2106. https://doi.org/10.1158/1078-0432.CCR-12-3325
Leone, Emanuela ; Morelli, Eugenio ; Di Martino, Maria T. ; Amodio, Nicola ; Foresta, Umberto ; Gullà, Annamaria ; Rossi, Marco ; Neri, Antonino ; Giordano, Antonio ; Munshi, Nikhil C. ; Anderson, Kenneth C. ; Tagliaferri, Pierosandro ; Tassone, Pierfrancesco. / Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 8. pp. 2096-2106.
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abstract = "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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AU - Gullà, Annamaria

AU - Rossi, Marco

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