Unique haploinsufficient role of the microRNA-processing molecule Dicer1 in a murine colitis-associated tumorigenesis model

PLoS One. 2013 Sep 2;8(9):e71969. doi: 10.1371/journal.pone.0071969. eCollection 2013.

Abstract

A widespread downregulated expression of microRNAs (miRNAs) is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and -suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Colitis / genetics
  • Colitis / metabolism*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Disease Models, Animal
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism*

Substances

  • MicroRNAs
  • Dicer1 protein, mouse
  • Ribonuclease III
  • DEAD-box RNA Helicases

Grants and funding

This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#22390058 and #2529307 to M. Otsuka, and #24390183 to K. Koike), by Health Sciences Research Grants of The Ministry of Health, Labour and Welfare of Japan (to K. Koike), grants from the Japan Foundation for Applied Enzymology, the Sagawa Foundation for Promotion of Cancer Research, the Cell Science Research Foundation, and the Japanese Society of Gastroenterology (to M. Otsuka.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.