Activin B promotes endometrial cancer cell migration by down-regulating E-cadherin via SMAD-independent MEK-ERK1/2-SNAIL signaling

High-risk type II endometrial cancers account for ~30% of cases but ~75% of deaths due, in part, to their tendency to metastasize. Histopathological studies of type II endometrial cancers (non-endometrioid, mostly serous) suggest overproduction of Activin B and down-regulation of E-cadherin, both of which are associated with reduced survival. Our previous studies have shown that Activin B increases the migration of type II endometrial Cancer cell lines. However, little is known about the relationship between Activin B signaling and E-cadherin in endometrial Cancer. We now demonstrate that Activin B treatment significantly decreases E-cadherin expression in both a time- and concentration-dependent manner in KLE and HEC-50 cell lines. Interestingly, these effects were not inhibited by knockdown of SMAD2, SMAD3 or SMAD4. Rather, the suppressive effects of Activin B on E-cadherin were mediated by MEK-ERK1/2-induced production of the transcription factor SNAIL. Importantly, activin B-induced cell migration was inhibited by forced-expression of E-cadherin or pre-treatment with the activin/TGF-β type I receptor inhibitor SB431542 or the MEK Inhibitor U0126. We have identified a novel SMAD-independent pathway linking enhanced Activin B signaling to reduced E-cadherin expression and increased migration in type II endometrial Cancer.

E-cadherin; ERK1/2; activin B; cell migration; serous endometrial cancer.