title: Integrin signaling potentiates transforming growth factor-beta 1 (TGF-β1) dependent down-regulation of E-Cadherin expression - Important implications for epithelial to mesenchymal transition (EMT) in renal cell carcinoma.
abstract: Signal transduction through the transforming growth factor-beta 1 (TGF-β1) pathway affects epithelial to mesenchymal transition (EMT), partly by modulation of E-Cadherin expression. The concurrent impact of extracellular matrix driven regulation of integrin signaling on EMT has not been well characterized. We assessed the cumulative effect and molecular mechanisms of TGF-β1 and integrin signal transduction on E-Cadherin in a renal cell cancer (RCC) model. Stimulation of RCC cells with TGF-β1 demonstrated a three-fold increased expression of integrin αv. A ligand of integrin αv-β3, (cyclopentapeptide containing Arginyl-Glycyl-Aspartic acid motif, RGD), was used to mimic integrin signaling. Treatment of cells with RGD and TGF-β1 demonstrated significantly greater E-cadherin depletion than either ligand alone. This cooperative action on E-Cadherin expression is regulated by transcription factor Snai1 and is followed on a cellular level by increased cellular mobility as evidenced in a wound healing assay. Subsequent silencing of potential downstream mediators of the cumulative action of RGD and TGF-β1 was carried out by small interfering RNA transfection and confirmed by Western blotting and/or RT-PCR. SiRNA mediated silencing of FAK and PINCH1 independently abrogated the cumulative effect of RGD and TGF-β1 on E-Cadherin expression. We have identified a novel mechanism through which extracellular matrix event transduction by integrins further augments TGF-β1 related effects on EMT. Molecular machinery involved in the integrin αv-TGF-β1 interplay may represent a therapeutic target in RCC.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: B
authors.initials: B
authors.lastname: Feldkoren
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: R
authors.initials: R
authors.lastname: Hutchinson
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Rapoport
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: A
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: V
authors.initials: V
authors.lastname: Margulis
mesh_terms: D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D015820:Cadherins; D016023:Integrins; D009842:Oligopeptides; D053773:Transforming Growth Factor beta1; C047981:arginyl-glycyl-aspartic acid
keywords: E-Cadherin expression; Epithelial to mesenchymal transition (EMT); Integrin αv (ITGAV); RGD; Renal cell cancer; Transforming growth factor-beta 1 (TGF-β1)