Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development

作者：Pichiorri Flavia^*; Suh Sung Suk; Rocci Alberto; De Luca Luciana; Taccioli Cristian; Santhanam Ramasamy; Zhou Wenchao; Benson Don M Jr; 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

来源：Cancer Cell, 2010, 18(4): 367-381.

DOI：10.1016/j.ccr.2010.09.005

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.

• 出版日期2010-10-19