title: Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells.
abstract: Epithelial-mesenchymal transition (EMT) plays a critical role in the progression of epithelial ovarian cancer (EOC). However, the mechanisms that regulate EMT in EOC are not fully understood. Here, we report that activation of Notch1 induces EMT in EOC cells as evidenced by downregulation of E-cadherin and cytokeratins, upregulation of Slug and Snail, as well as morphological changes. Interestingly, activation of Notch1 increases TGFβ/Smad signaling by upregulating the expression of TGFβ and TGFβ type 1 receptor. Time course experiments demonstrate that inhibition of Notch by DAPT (a γ-secretase inhibitor) decreases TGFβ-induced phosphorylation of receptor Smads at late, but not at early, timepoints. These results suggest that Notch activation plays a role in sustaining TGFβ/Smad signaling in EOC cells. Furthermore, inhibition of Notch by DAPT decreases TGFβ induction of Slug and repression of E-cadherin and knockdown of Notch1 decreases TGFβ-induced repression of E-cadherin, indicating that Notch is required, at least in part, for TGFβ-induced EMT in EOC cells. On the other hand, TGFβ treatment increases the expression of Notch ligand Jagged1 and Notch target gene HES1 in EOC cells. Functionally, the combination of Notch1 activation and TGFβ treatment is more potent in promoting motility and migration of EOC cells than either stimulation alone. Taken together, our results indicate that Notch and TGFβ form a reciprocal positive regulatory loop and cooperatively regulate EMT and promote EOC cell motility and migration.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; The first affiliated hospital, Shantou University Medical College, Shantou, Guangdong Province, China.
authors.forename: Jiesi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Saket
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Abul K
authors.initials: AK
authors.lastname: Azad
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Hai Chuan
authors.initials: HC
authors.lastname: Yu
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Roseline
authors.initials: R
authors.lastname: Godbout
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. Electronic address: yangxin@ualberta.ca.
authors.forename: YangXin
authors.initials: Y
authors.lastname: Fu
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D000072100:Jagged-1 Protein / Q000378:metabolism; D008024:Ligands; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D051880:Receptors, Notch / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D000072056:Transcription Factor HES-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D051880:Receptors, Notch; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta; C078493:HES1 protein, human; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: EMT; Epithelial ovarian cancer; Notch; TGFβ