miR-34 cooperates with p53 in suppression of prostate cancer by joint regulation of stem cell compartment

Cell Rep. 2014 Mar 27;6(6):1000-1007. doi: 10.1016/j.celrep.2014.02.023. Epub 2014 Mar 13.


The miR-34 family was originally found to be a direct target of p53 and is a group of putative tumor suppressors. Surprisingly, mice lacking all mir-34 genes show no increase in cancer formation by 18 months of age, hence placing the physiological relevance of previous studies in doubt. Here, we report that mice with prostate epithelium-specific inactivation of mir-34 and p53 show expansion of the prostate stem cell compartment and develop early invasive adenocarcinomas and high-grade prostatic intraepithelial neoplasia, whereas no such lesions are observed after inactivation of either the mir-34 or p53 genes alone by 15 months of age. Consistently, combined deficiency of p53 and miR-34 leads to acceleration of MET-dependent growth, self-renewal, and motility of prostate stem/progenitor cells. Our study provides direct genetic evidence that mir-34 genes are bona fide tumor suppressors and identifies joint control of MET expression by p53 and miR-34 as a key component of prostate stem cell compartment regulation, aberrations in which may lead to cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Growth Processes / physiology
  • Male
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neoplastic Stem Cells / pathology*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism


  • MIRN34a microRNA, mouse
  • MicroRNAs
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-met