Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis

Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10144-9. doi: 10.1073/pnas.1103735108. Epub 2011 Jun 6.


MicroRNA 21 (miR-21) is overexpressed in virtually all types of carcinomas and various types of hematological malignancies. To determine whether miR-21 promotes tumor development in vivo, we knocked out the miR-21 allele in mice. In response to the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate mouse skin carcinogenesis protocol, miR-21-null mice showed a significant reduction in papilloma formation compared with wild-type mice. We revealed that cellular apoptosis was elevated and cell proliferation was decreased in mice deficient of miR-21 compared to wild-type animals. In addition, we found that a large number of validated or predicted miR-21 target genes were up-regulated in miR-21-null keratinocytes, which are precursor cells to skin papillomas. Specifically, up-regulation of Spry1, Pten, and Pdcd4 when miR-21 was ablated coincided with reduced phosphorylation of ERK, AKT, and JNK, three major downstream effectors of Ras activation that plays a predominant role in DMBA-initiated skin carcinogenesis. These results provide in vivo evidence that miR-21 exerts its oncogenic function through negatively regulating its target genes.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / pharmacology
  • Animals
  • Apoptosis / genetics
  • Carcinogens / pharmacology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Epidermal Cells
  • Epidermis / drug effects
  • Epidermis / pathology
  • Epidermis / physiology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / physiology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Signal Transduction / physiology
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / pathology
  • Skin Neoplasms / physiopathology
  • Tetradecanoylphorbol Acetate / pharmacology
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Carcinogens
  • MIRN21 microRNA, mouse
  • MicroRNAs
  • 9,10-Dimethyl-1,2-benzanthracene
  • ras Proteins
  • Tetradecanoylphorbol Acetate