DLC1 negatively regulates angiogenesis in a paracrine fashion

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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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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Vascular Endothelial Growth Factor A
Hypoxia-Inducible Factor 1
Neoplasms
Up-Regulation
Down-Regulation
Focal Adhesions
Cell Shape
Mitogen-Activated Protein Kinase Kinases
Liver Neoplasms
RNA Interference
Actin Cytoskeleton
Epidermal Growth Factor Receptor
Cell Adhesion
Small Interfering RNA
Prostate
Prostatic Neoplasms
Carcinogenesis
Epithelial Cells
Phenotype
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

DLC1 negatively regulates angiogenesis in a paracrine fashion. / Shih, Yi Ping; Liao, Yi Chun; Lin, Yuan; Lo, Su Hao.

In: Cancer Research, Vol. 70, No. 21, 01.11.2010, p. 8270-8275.

Research output: Contribution to journalArticle

Shih, Yi Ping ; Liao, Yi Chun ; Lin, Yuan ; Lo, Su Hao. / DLC1 negatively regulates angiogenesis in a paracrine fashion. In: Cancer Research. 2010 ; Vol. 70, No. 21. pp. 8270-8275.
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