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Prediction and Validation of Gene Regulatory Elements Activated During Retinoic Acid Induced Embryonic Stem Cell Differentiation
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9-cis retinoic acid induces insulin-like growth factor binding protein-3 through DR-8 retinoic acid responsive

Yoon Soo Chang1, Jae Yong Cho, Hyun A Cho

  • 1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Cancer Biology & Therapy
|June 9, 2006
PubMed

Insights

9-cis retinoic acid (9cRA) inhibits non-small cell lung cancer (NSCLC) proliferation and upregulates insulin-like growth factor binding protein-3 (IGFBP-3) expression. This effect is mediated by retinoic acid receptor-beta (RAR-beta) binding to a specific element in the IGFBP-3 promoter.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Retinoic acids exhibit chemopreventive and therapeutic potential in neoplastic diseases.
  • Retinoic acids modulate insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) expression.
  • Retinoic acid receptor-beta (RAR-beta) is implicated in cancer pathways.

Purpose of the Study:

  • To investigate the effect of 9-cis retinoic acid (9cRA) on IGFBP-3 expression in non-small cell lung cancer (NSCLC) cells.
  • To elucidate the underlying molecular mechanisms involving retinoic acid receptor-beta (RAR-beta).

Main Methods:

  • Treatment of NSCLC cell lines with 9cRA.
  • Reporter gene assays using the human IGFBP-3 promoter.
  • Site-directed mutagenesis and deletion analysis to identify response elements.
  • Co-transfection assays with RAR-beta expression vectors and siRNA.

Main Results:

  • 9cRA inhibited proliferation of certain NSCLC cell lines, including H460 cells.
  • 9cRA induced IGFBP-3 expression in a dose- and time-dependent manner.
  • A retinoic acid responsive element (RARE) of DR-8 type was identified in the IGFBP-3 promoter (-534 to -445 region).
  • RAR-beta potentiated 9cRA-induced IGFBP-3 expression, while its depletion diminished the effect.

Conclusions:

  • 9cRA effectively inhibits NSCLC proliferation and upregulates IGFBP-3 expression.
  • IGFBP-3 gene expression is mediated by a DR-8 RARE in the proximal promoter region.
  • RAR-beta plays a crucial role in mediating the effects of 9cRA on IGFBP-3 expression, suggesting its potential as a tumor suppressor in NSCLC.

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