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Estrogen receptors in urogenital schistosomiasis and bladder cancer: Estrogen receptor alpha-mediated cell proliferation

2020-09Journal article Restricted access
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dc.contributor.authorBernardo, Carina
dc.contributor.authorSantos, Júlio
dc.contributor.authorCosta, Céu
dc.contributor.authorTavares, Ana
dc.contributor.authorAmaro, Teresina
dc.contributor.authorMarques, Igor
dc.contributor.authorGouveia, Maria João
dc.contributor.authorFélix, Vítor
dc.contributor.authorAfreixo, Vera
dc.contributor.authorBrindley, Paul J.
dc.contributor.authorCosta, José Manuel
dc.contributor.authorAmado, Francisco
dc.contributor.authorHelguero, Luisa
dc.contributor.authorSantos, Lúcio L.
dc.date.accessioned2021-03-31T16:02:06Z
dc.date.available2021-03-31T16:02:06Z
dc.date.issued2020-09
dc.description.abstractEstrogen-like metabolites have been identified in S. haematobium, the helminth parasite that causes urogenital schistosomiasis (UGS) and in patients´ blood and urine during UGS. Estrogen receptor (ER) activation is enriched in the luminal molecular subtype bladder cancer (BlaCa). To date, the significance of ER to these diseases remains elusive. We evaluated ERα and ERβ expression in UGS-related BlaCa (n = 27), UGS-related non-malignant lesions (n = 35), and noninfected BlaCa (n = 80). We investigated the potential of ERα to recognize S. haematobium-derived metabolites by docking and molecular dynamics simulations and studied ERα modulation in vitro using 3 BlaCa cell lines, T24, 5637 and HT1376. ERα was expressed in tumor and stromal cells in approximately 20% noninfected cases and in 30% of UGS-related BlaCa, predominantly in the epithelial cells. Overall, ERα expression was associated with features of tumor aggressiveness such as high proliferation and p53 positive expression. ERα expression correlated with presence of schistosome eggs. ERβ was widely expressed in both cohorts but weaker in UGS-related cases. molecular dynamics simulations of the 4 most abundant S. haematobium-derived metabolites revealed that smaller metabolites have comparable affinity for the ERα active state than 17β-estradiol, while the larger metabolites present higher affinity. Our in vitro findings suggested that ERα activation promotes proliferation in ERα expressing BlaCa cells and that this can be reverted with anti-estrogenic therapy. In summary, we report differential ER expression between UGS-related BlaCa and noninfected BlaCa and provide evidence supporting a role of active ERα during UGS and UGS-induced carcinogenesis.pt_PT
dc.description.abstractHighlights: Estrogen receptor (ERs) are expressed in both urogenital schistosomiasis and bladder cancer; ERα was associated with aggressive tumor features and presence of schistosome eggs; In silico analysis shows an agonistic putative action of S. haematobium-derived metabolites for ERα; ERα induced proliferation in bladder cancer cells can be reverted by anti-estrogens; Evidence suggests that activation of ERα could play a role in urogenital schistosomiasis and urogenital schistosomiasis-induced carcinogenesis.pt_PT
dc.description.sponsorshipPJB acknowledges support from award R01CA164719 from the National Cancer Institute (NCI), National Institutes of Health (NIH), USA.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationUrol Oncol. 2020 Sep;38(9):738.e23-738.e35. doi: 10.1016/j.urolonc.2020.04.022. Epub 2020 Jun 2.pt_PT
dc.identifier.doi10.1016/j.urolonc.2020.04.022pt_PT
dc.identifier.issn1078-1439
dc.identifier.urihttp://hdl.handle.net/10400.18/7614
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevier/ Society of Urologic Oncologypt_PT
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/abs/pii/S1078143920301587?via%3Dihubpt_PT
dc.subjectAnti-Estrogenspt_PT
dc.subjectBladder Cancerpt_PT
dc.subjectEstradiol-Like Metabolitespt_PT
dc.subjectEstrogen Receptorspt_PT
dc.subjectUGS-Related Bladder Cancerpt_PT
dc.subjectUrogenital Schistosomiasispt_PT
dc.subjectInfecções Sistémicas e Zoonosespt_PT
dc.titleEstrogen receptors in urogenital schistosomiasis and bladder cancer: Estrogen receptor alpha-mediated cell proliferationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage738.e35pt_PT
oaire.citation.issue9pt_PT
oaire.citation.startPage738.e23pt_PT
oaire.citation.titleUrologic Oncology: Seminars and Original Investigationspt_PT
oaire.citation.volume38pt_PT
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT

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