Journal
EXPERIMENTAL CELL RESEARCH
Volume 355, Issue 2, Pages 57-66Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2017.03.051
Keywords
Transforming growth factor-beta 1 (TGF-beta 1); RGD; Integrin alpha v (ITGAV); E-Cadherin expression; Epithelial to mesenchymal transition (EMT); Renal cell cancer
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Signal transduction through the transforming growth factor-beta 1 (TGF-beta 1) 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-beta 1 and integrin signal transduction on E-Cadherin in a renal cell cancer (RCC) model. Stimulation of RCC cells with TGF-beta 1 demonstrated a three-fold increased expression of integrin ay. A ligand of integrin alpha v-beta 3, (cyclopentapeptide containing Arginyl-Glycyl-Aspartic acid motif, RGD), was used to mimic integrin signaling. Treatment of cells with RGD and TGF-beta 1 demonstrated significantly greater E-cadherin depletion than either ligand alone. This cooperative action on E-Cadherin expression is regulated by transcription factor Snail 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-beta 1 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-beta 1 on E-Cadherin expression. We have identified a novel mechanism through which extracellular matrix event transduction by integrins further augments TGF-beta 1 related effects on EMT. Molecular machinery involved in the integrin alpha v-TGF-beta 1 interplay may represent a therapeutic target in RCC.
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