Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-β

Sheng Ru Shiou, Pran K. Datta, Punita Dhawan, Brian K. Law, Jonathan M. Yingling, Dan A. Dixon, R. Daniel Beauchamp

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Metastasis is a primary cause of mortality due to cancer. Early metastatic growth involves both a remodeling of the extracellular matrix surrounding tumors and invasion of tumors across the basement membrane. Up-regulation of extracellular matrix degrading proteases such as urokinase plasminogen activator (uPA) and matrix metalloproteinases has been reported to facilitate tumor cell invasion. Autocrine transforming growth factor-β (TGF-β) signaling may play an important role in cancer cell invasion and metastasis; however, the underlying mechanisms remain unclear. In the present study, we report that autocrine TGF-β supports cancer cell invasion by maintaining uPA levels through protein secretion. Interestingly, treatment of paracrine/exogenous TGF-β at higher concentrations than autocrine TGF-β further enhanced uPA expression and cell invasion. The enhanced uPA expression by exogenous TGF-β is a result of increased uPA mRNA expression due to RNA stabilization. We observed that both autocrine and paracrine TGF-β-mediated regulation of uPA levels was lost upon depletion of Smad4 protein by RNA interference. Thus, through the Smad pathway, autocrine TGF-β maintains uPA expression through facilitated protein secretion, thereby supporting tumor cell invasiveness, whereas exogenous TGF-β further enhances uPA expression through mRNA stabilization leading to even greater invasiveness of the cancer cells.

Original languageEnglish (US)
Pages (from-to)33971-33981
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number45
DOIs
StatePublished - Nov 10 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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