DLC1 negatively regulates angiogenesis in a paracrine fashion

Yi Ping Shih, Yi Chun Liao, Yuan Lin, Su Hao Lo

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8270-8275
Number of pages6
JournalCancer Research
Volume70
Issue number21
DOIs
StatePublished - Nov 1 2010

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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