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. 2017 Jun 15;355(2):57-66.
doi: 10.1016/j.yexcr.2017.03.051. Epub 2017 Mar 29.

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

B Feldkoren  1 , R Hutchinson  1 , Y Rapoport  1 , A Mahajan  1 , V Margulis  1
Affiliations

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

B Feldkoren et al. Exp Cell Res. .

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.

Keywords: E-Cadherin expression; Epithelial to mesenchymal transition (EMT); Integrin αv (ITGAV); RGD; Renal cell cancer; Transforming growth factor-beta 1 (TGF-β1).

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