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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

384 Scopus citations

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 languageAmerican English
Pages (from-to)367-381
Number of pages15
JournalCancer Cell
Volume18
Issue number4
DOIs
StatePublished - 19 Oct 2010

Bibliographical note

Funding Information:
We thank Kay Huebner for careful reading of the draft MS, Nicola Zanesi for helping with the animal procedures, Dorothee Wernicke for helpful scientific discussion, Michele Morara for statistical advice, Yuri Pekarsky for scientific advice, Guido Marcucci and Ramiro Garzon for scientific advice, and Sharon Palko for administrative support. We also thank Dr. Shaomeng Wang's laboratory for supplying MI-219 compound and Dr. Irene M. Ghobrial for providing MM1s GFP+/Luc+ cells. We are grateful for research support from the Ohio State University Targeted Investment in Excellence Award and the Kimmel Foundation award (F.P.).

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