TGFβ1 induces endometrial cancer cell adhesion and migration by up-regulating integrin αvβ3 via SMAD-independent MEK-ERK1/2 signaling

Endometrial cancer is the most common, and second most lethal, gynecological malignancy, and its rates of incidence and death are growing. This is likely attributable to increased numbers of high-risk type II endometrial cancers which account for similar to 30% of cases but similar to 75% of deaths due to their aggressive and metastatic behaviour. Histopathological and in vitro functional studies suggest that aberrant TGF beta 1 signaling may contribute to endometrial cancer development and the acquisition of invasive/metastatic characteristics. However, little is known about the cellular and molecular mechanisms of TGF beta 1 in high-risk endometrial cancers. In the present study, we examined the roles and mechanisms of TGF beta 1 on cell adhesion and motility in type II endometrial cancer cell lines, KLE and HEC-1B. We show that treatment with TGF beta 1 increases cell adhesion to vitronectin and transwell cell migration. We also demonstrate that TGF beta 1 treatment increases integrin beta 3 and alpha v mRNA and protein levels via SMAD-independent MEK-ERK1/2 signaling. Importantly, siRNA depletion or antibody mediated blocking of integrin alpha v beta 3 reversed the effects of TGF beta 1 on cell adhesion and migration. Our results suggest that TGF beta 1-MEK-ERK1/2-integrin alpha v beta 3 signaling could-contribute to the invasive behaviour of high-risk endometrial cancer by promoting cell adhesion and migration.