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The RUNX3 tumor suppressor upregulates Bim in gastric epithelial cells undergoing transforming growth factor

Takashi Yano1, Kosei Ito, Hiroshi Fukamachi

  • 1Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore.

Molecular and Cellular Biology
|June 2, 2006
PubMed

Insights

RUNX3 activates the proapoptotic gene Bim, crucial for TGF-beta-induced apoptosis in gastric cancer. Loss of RUNX3 reduces Bim expression and impairs apoptosis, highlighting its tumor suppressor role.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Transforming growth factor beta (TGF-beta) signaling pathway alterations are common in cancers.
  • RUNX3, a gastric tumor suppressor, is linked to the TGF-beta pathway.
  • Reduced apoptosis was previously observed in Runx3-/- gastric epithelial cells.

Purpose of the Study:

  • To investigate the role of RUNX3 in TGF-beta-induced apoptosis.
  • To determine if RUNX3 transcriptionally regulates the proapoptotic gene Bim.
  • To elucidate the mechanism by which RUNX3 influences gastric cancer tumorigenicity.

Main Methods:

  • Investigated RUNX3's effect on Bim expression in gastric cancer cell lines (SNU16, SNU719) treated with TGF-beta.
  • Analyzed the human Bim promoter for RUNX binding sites.
  • Utilized a dominant-negative RUNX3 construct to assess its impact on tumorigenicity and Bim expression.
  • Examined Bim expression and apoptosis levels in Runx3-/- and Bim-/- mouse gastric epithelium.
  • Compared TGF-beta signaling components in wild-type and Runx3-/- gastric epithelia.

Main Results:

  • RUNX3 transcriptionally activated the proapoptotic gene Bim in response to TGF-beta in gastric cancer cells.
  • RUNX binding sites in the human Bim promoter were essential for its activation.
  • Inhibition of Bim expression by a dominant-negative RUNX3 construct increased SNU16 cell tumorigenicity.
  • Bim was down-regulated and apoptosis reduced in Runx3-/- mouse gastric epithelium, mirroring Bim-/- phenotypes.
  • TGF-beta1 and receptor expression were comparable between wild-type and Runx3-/- gastric epithelia, but Bim was reduced in TGF-beta1-/- stomachs.

Conclusions:

  • RUNX3 is a key mediator of TGF-beta-induced apoptosis through transcriptional up-regulation of Bim.
  • RUNX3 functions as a tumor suppressor in gastric epithelium by promoting Bim expression and apoptosis.
  • The RUNX3-Bim axis is critical for TGF-beta-mediated tumor suppression in the gastric context.

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