Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development

Flavia Pichiorri, Sung Suk Suh, Alberto Rocci, Luciana De Luca, Cristian Taccioli, Ramasamy Santhanam, Wenchao Zhou, Don M. Benson, Craig Hofmainster, Hansjuerg Alder, Michela Garofalo, Gianpiero Di Leva, Stefano Volinia, Huey Jen Lin, Danilo Perrotti, Michael Kuehl, Rami I. Aqeilan, Antonio Palumbo, Carlo M. Croce

Research output: Contribution to journalArticle

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Abstract

In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.

Original languageEnglish
Pages (from-to)367-381
Number of pages15
JournalCancer Cell
Volume18
Issue number4
DOIs
Publication statusPublished - Oct 19 2010

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Multiple Myeloma
Down-Regulation
MicroRNAs
Sequence Deletion
Plasma Cells
B-Lymphocytes
Bone Marrow
mouse MIRN194 microRNA
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Pichiorri, F., Suh, S. S., Rocci, A., De Luca, L., Taccioli, C., Santhanam, R., ... Croce, C. M. (2010). Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell, 18(4), 367-381. https://doi.org/10.1016/j.ccr.2010.09.005

Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. / Pichiorri, Flavia; Suh, Sung Suk; Rocci, Alberto; De Luca, Luciana; Taccioli, Cristian; Santhanam, Ramasamy; Zhou, Wenchao; Benson, Don M.; Hofmainster, Craig; Alder, Hansjuerg; Garofalo, Michela; Di Leva, Gianpiero; Volinia, Stefano; Lin, Huey Jen; Perrotti, Danilo; Kuehl, Michael; Aqeilan, Rami I.; Palumbo, Antonio; Croce, Carlo M.

In: Cancer Cell, Vol. 18, No. 4, 19.10.2010, p. 367-381.

Research output: Contribution to journalArticle

Pichiorri, F, Suh, SS, Rocci, A, De Luca, L, Taccioli, C, Santhanam, R, Zhou, W, Benson, DM, Hofmainster, C, Alder, H, Garofalo, M, Di Leva, G, Volinia, S, Lin, HJ, Perrotti, D, Kuehl, M, Aqeilan, RI, Palumbo, A & Croce, CM 2010, 'Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development', Cancer Cell, vol. 18, no. 4, pp. 367-381. https://doi.org/10.1016/j.ccr.2010.09.005
Pichiorri, Flavia ; Suh, Sung Suk ; Rocci, Alberto ; De Luca, Luciana ; Taccioli, Cristian ; Santhanam, Ramasamy ; Zhou, Wenchao ; Benson, Don M. ; Hofmainster, Craig ; Alder, Hansjuerg ; Garofalo, Michela ; Di Leva, Gianpiero ; Volinia, Stefano ; Lin, Huey Jen ; Perrotti, Danilo ; Kuehl, Michael ; Aqeilan, Rami I. ; Palumbo, Antonio ; Croce, Carlo M. / Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. In: Cancer Cell. 2010 ; Vol. 18, No. 4. pp. 367-381.
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AU - Croce, Carlo M.

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