Role of β5-integrin in epithelial-mesenchymal transition in response to TGF-β

Abstract

Epithelial-mesenchymal-transition (EMT) in response to TGFβ contributes to normal development, wound healing and tumor progression. The present study provides evidence for a critical role of β5-integrin in the TGFβ-induced EMT and the tumorigenic potential of carcinoma cells. We show that the αvβ-integrin subunits are upregulated during the TGFβ-induced EMT and this response requires Smad transcription factors. Depletion of αv-integrin by siRNA blocked the EMT response whereas knock-down of β1-integrin had no effect. Importantly, depletion of β5-integrin blocked the TGFβ-induced EMT impairing adhesion to cell-matrix and integrin signaling, but did not change expression of E-cadherin and TGFβ-target genes. Accordingly, the EMT process and integrin signaling were blocked by cRGD peptide interfering with cell-matrix adhesion or by inhibition of focal adhesion kinase, indicating the importance of β5-integrin-mediated adhesions in EMT. Finally, depletion of β5-integrin significantly reduced invasiveness of breast carcinoma cells. Thus, the β5-integrin adhesions contribute to the TGFβ-induced EMT and the tumorigenic potential of carcinoma cells.

Signaling mechanism of cell adhesion molecules in breast cancer metastasis: potential therapeutic targets

“…On the other hand, integrin a5b1 can induce angiopoietin-2-stimulated cell migration through integrin a5b1/integrin-linked kinase (ILK)/Akt and GSK-3beta/ Snail/E-cadherin signaling pathways [76]. It is observed that depletion of b5 integrin blocked the TGFb-induced EMT impairing adhesion to ECM and integrin signaling, but did not change expression of E-cadherin and TGFb-targeted genes, indicating b5 integrin is required for TGFb-induced EMT through the adhesion to ECM and the initiation of downstream signaling to focal adhesion kinase (FAK) [77]. In addition, integrins control cytoskeletal organization, cell migration, and invasion through one or more outside-in signaling cascades.…”

The emerging role of the TGFβ tumor suppressor pathway in pancreatic cancer

“…The same signaling and stem cell pathways cooperate with the TGFβ pathway in both its tumor suppressor activity and its capacity to induce epithelial-mesenchymal transition (EMT). 24,25 A possibility is that these two facets of the TGFβ pathway play distinct roles on the two pancreatic cell programs. The two apparently opposite features of the TGFβ pathway are also observed with other signaling nodes, such as caveolin-1, which can regulate pancreatic cell behavior.…”

Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer

“…80,81 Multiple reports demonstrate that the very same transcription factors (i.e., SNAI1, SNAI2, TWIST1), adhesive structures (i.e., aν-β-integrin family) and signaling pathways (i.e., Tgfβ, Notch, Hedgehog) controlling defined EMT programs are also responsible for regulating tumor progression. 15,82 For instance, loss of E-cadherin expression is a hallmark of metastatic carcinoma and expression of the transcriptional repressor of E-cadherin SNAI1 correlates with poor survival rates. Additionally, SNAI1 expression levels are elevated at the invading front of colorectal tumors.…”