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Translational Inhibition of Slug by Pdcd4 Contributes to Invasion Inhibition in Colorectal Cancer Cells.

Qing Wang1, Wei He2, Shilong Han1,3

  • 1Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.

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Summary

Programmed cell death 4 (Pdcd4) suppresses colorectal cancer (CRC) invasion by inhibiting Slug translation. Loss of Pdcd4 increases Slug protein, promoting CRC cell invasion and metastasis.

Keywords:
E‐cadherinPdcd4Slug colorectal cancereIF4Ainvasion

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis

Background:

  • Colorectal cancer (CRC) metastasis is a primary cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion.
  • Programmed cell death 4 (Pdcd4) is a tumor suppressor that inhibits translation via eukaryotic initiation factor 4A (eIF4A).
  • Pdcd4 suppresses Snail expression and EMT in CRC cells, but its direct regulation of Slug, another key EMT factor, is unknown.

Purpose of the Study:

  • To investigate whether Pdcd4 directly regulates Slug, a critical transcription factor in EMT.
  • To elucidate the translational control mechanism of Slug by Pdcd4 in colorectal cancer cells.

Main Methods:

  • Knockdown of Pdcd4 and Slug using shRNA and siRNA in CRC cells.
  • Sucrose gradient fractionation to assess SLUG translation.
  • Luciferase reporter assay using the SLUG 5' untranslated region (5'UTR) to determine translational regulation.
  • Matrigel invasion assays to evaluate the role of Slug in CRC cell invasion.

Main Results:

  • Pdcd4 knockdown increased Slug protein levels without affecting SLUG mRNA levels, indicating translational suppression.
  • Pdcd4 knockdown enhanced SLUG 5'UTR activity, confirming the 5'UTR's role in translational repression.
  • Pdcd4 overexpression reduced Slug protein and restored E-cadherin expression; Slug knockdown in Pdcd4-deficient cells rescued E-cadherin and reduced invasion.

Conclusions:

  • Pdcd4 translationally downregulates Slug expression in colorectal cancer cells.
  • This translational repression by Pdcd4 suppresses Slug-mediated invasion and metastasis.
  • Pdcd4 acts as a suppressor of colorectal cancer invasion by controlling Slug translation.