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

Cancer Cell. 2010 Oct 19;18(4):367-81. doi: 10.1016/j.ccr.2010.09.005.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chromosomes, Human, Pair 11 / genetics
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Down-Regulation / drug effects
  • Down-Regulation / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Homeostasis / drug effects
  • Homeostasis / genetics*
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • MicroRNAs / genetics*
  • Models, Biological
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Mutagens / toxicity
  • Neoplasm Invasiveness
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • MicroRNAs
  • Mutagens
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Insulin-Like Growth Factor I
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Receptor, IGF Type 1