title: Growth differentiation factor 8 induces SKOV3 ovarian cancer cell migration and E-cadherin down-regulation.
abstract: Epithelial ovarian cancer is the most lethal gynecological malignancy because most women present with late stage disseminated disease. Epithelial-mesenchymal transition (EMT) is characterized by the down-regulation of E-cadherin and up-regulation of N-cadherin, and is a crucial event in the pathogenesis of ovarian cancer. Transforming growth factor-β (TGF-β) is a major regulator of EMT in many normal and neoplastic cell types. Growth differentiation factor 8 (GDF8), which also activates TGF-β-like SMAD2/3 signaling, is best known for negatively regulating muscle growth. Though recent studies suggest that GDF8 enhances placental trophoblast cell migration, little is known about the role of GDF8 in EMT and cancer metastasis. We hypothesized that GDF8 could enhance ovarian cancer cell migration by inducing EMT. Here we demonstrate for the first time that GDF8 down-regulates E-cadherin but does not alter N-cadherin in SKOV3 ovarian cancer cells. This effect is abolished by the activin receptor-like kinase (ALK)4/5/7 inhibitor SB431542 or siRNA-mediated knockdown of ALK5, whereas knockdown of ALK4 is only partially inhibitory. GDF8 treatment increases the phosphorylation of SMAD2/3 and up-regulates the E-cadherin transcriptional repressors Snail and Slug; and these effects are abolished by pre-treatment with SB431542. Knockdown of common SMAD4 fully reverses the effects of GDF8 on E-cadherin and partially attenuates its effects on Snail and Slug. Importantly, GDF8 treatment increases SKOV3 cell migration and this effect is blocked by SB431542. Our study suggests that GDF8 promotes ovarian cancer cell migration via ALK4/5-SMAD2/3-E-cadherin signaling.
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Zhao
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: 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: 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: Hsun-Ming
authors.initials: HM
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. Electronic address: peter.leung@ubc.ca.
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006801:Humans; D055435:Myostatin / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C525911:MSTN protein, human; D055435:Myostatin; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
keywords: Cell migration; E-cadherin; GDF8; Ovarian cancer; SMAD2/3