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

Shiou SR, Datta PK, Dhawan P, Law BK, Yingling JM, Dixon DA, Beauchamp RD
J Biol Chem. 2006 281 (45): 33971-81

PMID: 16959768 · DOI:10.1074/jbc.M607010200

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-beta (TGF-beta) 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-beta supports cancer cell invasion by maintaining uPA levels through protein secretion. Interestingly, treatment of paracrine/exogenous TGF-beta at higher concentrations than autocrine TGF-beta further enhanced uPA expression and cell invasion. The enhanced uPA expression by exogenous TGF-beta is a result of increased uPA mRNA expression due to RNA stabilization. We observed that both autocrine and paracrine TGF-beta-mediated regulation of uPA levels was lost upon depletion of Smad4 protein by RNA interference. Thus, through the Smad pathway, autocrine TGF-beta maintains uPA expression through facilitated protein secretion, thereby supporting tumor cell invasiveness, whereas exogenous TGF-beta further enhances uPA expression through mRNA stabilization leading to even greater invasiveness of the cancer cells.

MeSH Terms (23)

Autocrine Communication Blotting, Northern Breast Neoplasms Cell Membrane Cell Proliferation Collagen Drug Combinations Female Genes, Dominant Humans Immunoblotting Laminin Matrix Metalloproteinase 9 Neoplasm Invasiveness Paracrine Communication Plasminogen Activator Inhibitor 1 Proteoglycans Receptors, Transforming Growth Factor beta RNA Stability Smad4 Protein Transforming Growth Factor beta Tumor Cells, Cultured Urokinase-Type Plasminogen Activator

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