title: Activin B promotes endometrial cancer cell migration by down-regulating E-cadherin via SMAD-independent MEK-ERK1/2-SNAIL signaling.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Klausen
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Jung-Chien
authors.initials: JC
authors.lastname: Cheng
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D028341:Activins / Q000378:metabolism*; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C000604407:SNAI1 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D000071250:Snail Family Transcription Factors; C044147:activin B; D028341:Activins; D048049:Extracellular Signal-Regulated MAP Kinases; D048728:MAP Kinase Kinase Kinase 1
keywords: E-cadherin; ERK1/2; activin B; cell migration; serous endometrial cancer