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DLC1 negatively regulates angiogenesis in a paracrine fashion

Yi-Ping Shih1, Yi-Chun Liao, Yuan Lin

  • 1Department of Biochemistry and Molecular Medicine, Center for Tissue Regeneration and Repair, University of California-Davis, Sacramento, California 95817, USA.

Cancer Research
|September 24, 2010
PubMed

Insights

Loss of DLC1 tumor suppressor in prostate cells promotes angiogenesis via VEGF upregulation, not direct tumor growth. This suggests DLC1 loss acts as a "second hit" in cancer progression.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • The Rho GTPase-activating protein DLC1 functions as a tumor suppressor, frequently deleted in liver cancer and downregulated in other malignancies.
  • DLC1 regulates critical cellular processes including the actin cytoskeleton, cell shape, adhesion, migration, and proliferation.

Purpose of the Study:

  • To investigate the tumor suppressive functions of DLC1 by silencing it in nonmalignant prostate epithelial cells.
  • To elucidate the molecular mechanisms underlying DLC1's role in prostate cancer development and progression.

Main Methods:

  • Small hairpin RNA (shRNA) was used to silence DLC1 expression in prostate epithelial cells.
  • Vascular Endothelial Growth Factor (VEGF) and Hypoxia-Inducible Factor 1α (HIF-1α) levels were assessed following DLC1 silencing.
  • Signaling pathways involving Epidermal Growth Factor Receptor (EGFR), MAP/ERK kinase (MEK), and RhoA were analyzed.

Main Results:

  • DLC1 silencing did not promote aggressive tumor cell growth phenotypes.
  • DLC1 silencing led to increased pro-angiogenic responses, evidenced by Vascular Endothelial Growth Factor (VEGF) upregulation.
  • VEGF upregulation was associated with increased accumulation and nuclear localization of Hypoxia-Inducible Factor 1α (HIF-1α).
  • Modulation of VEGF by DLC1 involved EGFR-MAP/ERK kinase-HIF-1 signaling, independent of RhoA pathways.

Conclusions:

  • Loss of DLC1 in prostate cells promotes angiogenesis through VEGF upregulation, potentially via EGFR-MAPK-HIF-1 signaling.
  • Clinical data shows a significant correlation between VEGF upregulation and DLC1 downregulation in prostate cancers.
  • The downregulation of DLC1 may act as a critical 'second hit' facilitating tumor angiogenesis in a paracrine manner during tumorigenesis.

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