Induction of integrin β3 by sustained ERK activity promotes the invasiveness of TGFβ-induced mesenchymal tumor cells.

The emerging roles of integrin β3 in the epithelial-mesenchymal transition (EMT) and drug resistance underline its significance in cancer metastasis and recurrence. However, the molecular mechanism underlying the distinctive expression of integrin β3 is less understood. In the present report, we demonstrated that repetitive exposure to transforming growth factor β (TGFβ), a potent inducer of the EMT, significantly increased the expression of integrin β3 in A549 lung cancer cells with distinct mesenchymal properties, such as actin filament reorganization and invasiveness. Notably, integrin β3 expression was associated to cancer cell invasion and migration, and was determined not by Smad4-dependent pathways but by sustained ERK1/2 activity in the mesenchymal cancer cells. These data suggest that ERK1/2 plays an important role in mediating non-canonical TGFβ signal pathways for integrin β3 expression. Therefore, the targeting of the MEK/ERK activity seems to be a promising therapeutic approach to suppressing EMT-associated cancer progression that potentially occurs in TGFβ-enriched microenvironments, which would lead to the suppression of the metastatic potential of integrin β3-positive cancer cells.