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

作者：Xiong Siyuan; Klausen Christian; Cheng Jung Chien; Leung Peter C K

来源：Oncotarget, 2016, 7(26): 40060-40072.

DOI：10.18632/oncotarget.9483

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

High-risk type II endometrial cancers account for similar to 30% of cases but similar to 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-beta 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.

• 出版日期2016-6-28