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.
['Xiong|Siyuan|S|', 'Klausen|Christian|C|', 'Cheng|Jung-Chien|JC|', 'Leung|Peter C K|PC|']
D028341:Activins D015703:Antigens, CD D015820:Cadherins D045744:Cell Line, Tumor D002465:Cell Movement D016889:Endometrial Neoplasms D048049:Extracellular Signal-Regulated MAP Kinases D005260:Female D006801:Humans D048728:MAP Kinase Kinase Kinase 1 D009362:Neoplasm Metastasis D034741:RNA, Small Interfering D015398:Signal Transduction D051899:Smad2 Protein D051900:Smad3 Protein D051901:Smad4 Protein D000071250:Snail Family Transcription Factors
activin B cell migration E-cadherin ERK1/2 serous endometrial cancer