DLC1 negatively regulates angiogenesis in a paracrine fashion

Cancer Res. 2010 Nov 1;70(21):8270-5. doi: 10.1158/0008-5472.CAN-10-1174. Epub 2010 Sep 22.

Abstract

The Rho GTPase-activating protein DLC1 is a tumor suppressor that is often deleted in liver cancer and downregulated in other cancers. DLC1 regulates the actin cytoskeleton, cell shape, adhesion, migration, and proliferation through its Rho GTPase-activating protein activity and focal adhesion localization. In this study, we silenced DLC1 in nonmalignant prostate epithelial cells to explore its tumor suppression functions. Small hairpin RNA-mediated silencing of DLC1 was insufficient to promote more aggressive phenotypes associated with tumor cell growth. In contrast, DLC1 silencing promoted pro-angiogenic responses through vascular endothelial growth factor (VEGF) upregulation, accompanied by the accumulation of hypoxia-inducible factor 1α and its nuclear localization. Notably, modulation of VEGF expression by DLC1 was dependent on epidermal growth factor receptor-MAP/ERK kinase-hypoxia-inducible factor 1 signaling but on RhoA pathways. Clinically, VEGF upregulation is a highly significant event in prostate cancers in which DLC1 is downregulated. Thus, our results strongly suggest that loss of DLC1 may serve as a "second hit" in promoting angiogenesis in a paracrine fashion during tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aorta / cytology
  • Aorta / metabolism
  • Blotting, Western
  • Cell Adhesion
  • Cell Movement
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • GTPase-Activating Proteins / physiology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Paracrine Communication*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tissue Array Analysis
  • Tumor Suppressor Proteins / physiology*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • DLC1 protein, human
  • GTPase-Activating Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • rhoA GTP-Binding Protein