title: Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen.
abstract: Urocortin (UCN1) peptide shares structural and functional homology with corticotropin-releasing factor (CRF). UCN1 is significantly reduced in endometrial adenocarcinoma compared to healthy controls. However, there are no data which evaluate the effects of UCN1 in the endometrium, or how it is modulated. We used proliferation and transwell assays to determine the effect of UCN1 on the proliferation and migration of Ishikawa and HEC1A cells. We also determined the expression levels of UCN1 and its receptors produced by estrogen receptor agonists, and the effect of UCN1 on estrogen receptor expression, using quantitative polymerase chain reaction. UCN1 suppressed migration of endometrial cancer cells in vitro. This effect appears to be specific to CRF receptor 2 (CRFR2), as selective antagonism of CRFR2 but not CRFR1 completely eliminated suppression of migration. Activation of ERA reduced UCN1 expression, but only had a small effect on the expression of CRFR1. However, expression of CRFR2 was more notably reduced at both the mRNA and protein levels by activation of ERB. UCN1 in turn reduced both ERA and ERB expression, as assessed by real-time quantitative PCR. We demonstrate that UCN1 significantly suppresses the migration of endometrial cancer cells but has no effect on their proliferation. Thus, loss of UCN1 in endometrial cancer may promote invasion and metastatic spread. There is a complex relationship between the UCN1 system and estrogen receptors, which may provide insights into endometrial carcinogenesis, a disease known to be driven by estrogen excess.
authors.affiliation: Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL, United Kingdom.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Owens
authors.affiliation: Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL, United Kingdom.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Lawrence
authors.affiliation: Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL, United Kingdom.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Jackson
authors.affiliation: Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, St Mary's Hospital, University of Manchester, Oxford Road, Manchester, M13 9WL, United Kingdom.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Crosbie
authors.affiliation: Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL, United Kingdom.
authors.forename: Berna S
authors.initials: BS
authors.lastname: Sayan
authors.affiliation: Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, St Mary's Hospital, University of Manchester, Oxford Road, Manchester, M13 9WL, United Kingdom.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.affiliation: Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Townsend
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D054832:Urocortins / Q000235:genetics / Q000378:metabolism*
chemical_list: C101531:CRF receptor type 2; C506487:ESR1 protein, human; C000600034:ESR2 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018019:Receptors, Corticotropin-Releasing Hormone; C576814:UCN protein, human; D054832:Urocortins
keywords: CRF receptors; endometrial cancer; estrogen receptor; urocortin