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The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2

Lisa E Young1, Ashleigh E Moore, Lena Sokol

  • 1Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA.

Molecular Cancer Research : MCR
|November 4, 2011
PubMed

Insights

MicroRNA-16 (miR-16) normally degrades prostaglandin synthase COX-2 messenger RNA (mRNA) in the intestine. In colorectal cancer, reduced miR-16 and increased HuR protein disrupt this process, promoting tumor growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Post-transcriptional Regulation

Background:

  • Elevated cyclooxygenase-2 (COX-2) expression is common in colorectal cancer.
  • In healthy cells, COX-2 messenger RNA (mRNA) decay is mediated by an adenylate- and uridylate (AU)-rich element (ARE) in its 3'-untranslated region (3'-UTR).
  • This decay mechanism is impaired in colorectal tumors.

Purpose of the Study:

  • To investigate the role of microRNA (miRNA) in regulating COX-2 mRNA decay via the 3'-UTR ARE.
  • To determine the impact of miR-16 and HuR on COX-2 expression in colorectal cancer.

Main Methods:

  • Identified miR-16 binding to the COX-2 3'-UTR using molecular assays.
  • Quantified miR-16 levels in colorectal cancer cells and tumors.
  • Assessed the effect of miR-16 expression on COX-2 and prostaglandin synthesis.
  • Investigated the interaction between HuR, miR-16, and COX-2 mRNA using ribonucleoprotein immunoprecipitation and cellular localization studies.

Main Results:

  • miR-16 directly binds to the COX-2 3'-UTR, promoting mRNA decay and inhibiting COX-2 expression.
  • Colorectal cancer cells and tumors exhibit approximately twofold lower miR-16 levels.
  • Overexpressed cytoplasmic HuR in tumors stabilizes COX-2 mRNA, antagonizing miR-16's decay-promoting function.
  • HuR directly interacts with miR-16, leading to miR-16 downregulation.

Conclusions:

  • miR-16 is a key post-transcriptional regulator of COX-2 expression.
  • Elevated HuR levels in colorectal cancer counteract miR-16 activity, contributing to COX-2 overexpression.
  • These findings offer a novel explanation for the loss of miR-16 and altered mRNA decay in colorectal tumors.

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