Silencing of DLC1 upregulates PAI-1 expression and reduces migration in normal prostate cells

Yi Ping Shih, Yoshikazu Takada, Su Hao Lo

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Deleted in liver cancer 1 (DLC1) is a GTPase-activating protein (GAP) domain containing tumor suppressor that localizes to focal adhesions. In cancer cells, loss of DLC1 is known to enhance cancer cell migration. However, the role of DLC1 in normal cell migration has not been well studied. Here, we show that silencing of DLC1 (shDLC1) in normal prostate epithelial cells reduces cell migration in both Transwell and wound-healing assays. This migration defect is mainly due to upregulation of plasminogen activator inhibitor 1 (PAI-1). Silencing of PAI-1 rescues the shDLC1-reduced migration phenotype. Reexpression of DLC1 suppresses PAI-1 and restores the migration defect as well. In contrast, DLC1-K714E (GAP inactive) mutant neither decreases the PAI-1 level nor rescues the shDLC1 migration defect. Interestingly, DLC1-Y442F (tensin-binding and focal adhesion-localizing defective) mutant is able to suppress PAI-1 expression but does not restore the migration defect. Furthermore, PAI- 1 upregulation in shDLC1 cells is EGFR-MEK pathway dependent and is able to promote in vitro angiogenesis. Together, our results show that at least the following two new mechanisms are involved in DLC1-mediated normal cell migration: (i) DLC1 modulates the expression of PAI-1, which is a negative regulator for cell migration, in a GAP domain and EGFR-MEK-dependent manner and (ii) Independent of PAI-1, the interaction of DLC1 with tensin members positively regulates cell migration.

Original languageEnglish
Pages (from-to)34-39
Number of pages6
JournalMolecular Cancer Research
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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