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Multiple microRNAs induced by Cdx1 suppress Cdx2 in human colorectal tumour cells

Takanobu Tagawa1, Takeshi Haraguchi, Hiroaki Hiramatsu

  • 1Division of Host-Parasite Interaction, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku Tokyo 108-8639, Japan.

The Biochemical Journal
|August 2, 2012
PubMed

Insights

Caudal-type homeobox (Cdx) 1 suppresses Cdx2 in colorectal cells by inducing microRNAs that degrade CDX2 mRNA. This highlights a novel miRNA role in maintaining cellular homeostasis by regulating transcription factor levels.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Caudal-type homeobox (Cdx) 1 and Cdx2 are key transcription factors for intestinal and colorectal epithelial differentiation.
  • Previous studies indicate an inverse correlation between Cdx1 and Cdx2 levels in mice.
  • The mechanism by which Cdx1 suppresses Cdx2 in human colorectal cancer cells remained unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying Cdx1-mediated suppression of Cdx2.
  • To identify specific microRNAs involved in this regulatory pathway.
  • To understand the role of microRNAs in maintaining homeostasis of transcription factor families.

Main Methods:

  • Utilized microarray analysis to identify microRNAs upregulated by exogenous Cdx1 expression.
  • Performed computational prediction and experimental validation of microRNA binding sites on CDX2 mRNA 3'UTR.
  • Employed site-directed mutagenesis to confirm the role of specific microRNA binding sites in Cdx2 suppression.

Main Results:

  • Exogenous Cdx1 expression induced several microRNAs in SW480 colorectal cancer cells.
  • miR-9, miR-16, and miR-22 were identified as direct suppressors of Cdx2 by binding to its 3' untranslated region (UTR).
  • Mutating miR-9 and miR-16 binding sites in the CDX2 3'UTR blocked Cdx2 suppression, confirming their functional importance.

Conclusions:

  • MicroRNAs play a significant role in regulating Cdx2 levels, induced by Cdx1 expression.
  • This study reveals a novel mechanism where microRNAs contribute to cellular homeostasis by limiting transcription factor levels within the same gene family.
  • The findings provide insights into the intricate regulatory networks governing colorectal epithelial cell differentiation and tumor suppression.

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