title: Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-beta.
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-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.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2730, USA.
authors.forename: Sheng-Ru
authors.initials: SR
authors.lastname: Shiou
authors.forename: Pran K
authors.initials: PK
authors.lastname: Datta
authors.forename: Punita
authors.initials: P
authors.lastname: Dhawan
authors.forename: Brian K
authors.initials: BK
authors.lastname: Law
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Yingling
authors.forename: Dan A
authors.initials: DA
authors.lastname: Dixon
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Beauchamp
mesh_terms: D019898:Autocrine Communication; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D007797:Laminin; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011509:Proteoglycans; D020871:RNA Stability; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D017395:Plasminogen Activator Inhibitor 1; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C059485:matrigel; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9