Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis

BackgroundHepatocellular Carcinoma (HCC) is a sexually dimorphic cancer, with female sex being independently protective against HCC incidence and progression. The aim of our study was to understand the mechanism of estrogen receptor signaling in driving sex differences in hepatocarcinogenesis.Method...

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Auteurs principaux:	Mamatha Bhat, Elisa Pasini, Chiara Pastrello, Marc Angeli, Cristina Baciu, Mark Abovsky, Angella Coffee, Oyedele Adeyi, Max Kotlyar, Igor Jurisica
Format:	article
Langue:	EN
Publié:	Frontiers Media S.A. 2021
Sujets:	estrogen hepatocellular carcinoma high-throughput network analysis Wnt/b-catenin ESR1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Accès en ligne:	https://doaj.org/article/bcad94a7b6a3471bb30f1db3e5daad2f
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spelling	oai:doaj.org-article:bcad94a7b6a3471bb30f1db3e5daad2f2021-11-22T05:15:17ZEstrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis2234-943X10.3389/fonc.2021.777834https://doaj.org/article/bcad94a7b6a3471bb30f1db3e5daad2f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.777834/fullhttps://doaj.org/toc/2234-943XBackgroundHepatocellular Carcinoma (HCC) is a sexually dimorphic cancer, with female sex being independently protective against HCC incidence and progression. The aim of our study was to understand the mechanism of estrogen receptor signaling in driving sex differences in hepatocarcinogenesis.MethodsWe integrated 1,268 HCC patient sample profiles from publicly available gene expression data to identify the most differentially expressed genes (DEGs). We mapped DEGs into a physical protein interaction network and performed network topology analysis to identify the most important proteins. Experimental validation was performed in vitro on HCC cell lines, in and in vivo, using HCC mouse model.ResultsWe showed that the most central protein, ESR1, is HCC prognostic, as increased ESR1 expression was protective for overall survival, with HR=0.45 (95%CI 0.32-0.64, p=4.4E-06), and was more pronounced in women. Transfection of HCC cell lines with ESR1 and exposure to estradiol affected expression of genes involved in the Wnt/β-catenin signaling pathway. ER-α (protein product of ESR1) agonist treatment in a mouse model of HCC resulted in significantly longer survival and decreased tumor burden (p<0.0001), with inhibition of Wnt/β-Catenin signaling. In vitro experiments confirmed colocalization of β-catenin with ER-α, leading to inhibition of β-catenin-mediated transcription of target genes c-Myc and Cyclin D1.ConclusionCombined, the centrality of ESR1 and its inhibition of the Wnt/β-catenin signaling axis provide a biological rationale for protection against HCC incidence and progression in women.Mamatha BhatMamatha BhatMamatha BhatMamatha BhatElisa PasiniChiara PastrelloChiara PastrelloMarc AngeliCristina BaciuMark AbovskyMark AbovskyAngella CoffeeOyedele AdeyiMax KotlyarMax KotlyarIgor JurisicaIgor JurisicaIgor JurisicaIgor JurisicaIgor JurisicaFrontiers Media S.A.articleestrogenhepatocellular carcinomahigh-throughputnetwork analysisWnt/b-cateninESR1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	estrogen hepatocellular carcinoma high-throughput network analysis Wnt/b-catenin ESR1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	estrogen hepatocellular carcinoma high-throughput network analysis Wnt/b-catenin ESR1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mamatha Bhat Mamatha Bhat Mamatha Bhat Mamatha Bhat Elisa Pasini Chiara Pastrello Chiara Pastrello Marc Angeli Cristina Baciu Mark Abovsky Mark Abovsky Angella Coffee Oyedele Adeyi Max Kotlyar Max Kotlyar Igor Jurisica Igor Jurisica Igor Jurisica Igor Jurisica Igor Jurisica Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis
description	BackgroundHepatocellular Carcinoma (HCC) is a sexually dimorphic cancer, with female sex being independently protective against HCC incidence and progression. The aim of our study was to understand the mechanism of estrogen receptor signaling in driving sex differences in hepatocarcinogenesis.MethodsWe integrated 1,268 HCC patient sample profiles from publicly available gene expression data to identify the most differentially expressed genes (DEGs). We mapped DEGs into a physical protein interaction network and performed network topology analysis to identify the most important proteins. Experimental validation was performed in vitro on HCC cell lines, in and in vivo, using HCC mouse model.ResultsWe showed that the most central protein, ESR1, is HCC prognostic, as increased ESR1 expression was protective for overall survival, with HR=0.45 (95%CI 0.32-0.64, p=4.4E-06), and was more pronounced in women. Transfection of HCC cell lines with ESR1 and exposure to estradiol affected expression of genes involved in the Wnt/β-catenin signaling pathway. ER-α (protein product of ESR1) agonist treatment in a mouse model of HCC resulted in significantly longer survival and decreased tumor burden (p<0.0001), with inhibition of Wnt/β-Catenin signaling. In vitro experiments confirmed colocalization of β-catenin with ER-α, leading to inhibition of β-catenin-mediated transcription of target genes c-Myc and Cyclin D1.ConclusionCombined, the centrality of ESR1 and its inhibition of the Wnt/β-catenin signaling axis provide a biological rationale for protection against HCC incidence and progression in women.
format	article
author	Mamatha Bhat Mamatha Bhat Mamatha Bhat Mamatha Bhat Elisa Pasini Chiara Pastrello Chiara Pastrello Marc Angeli Cristina Baciu Mark Abovsky Mark Abovsky Angella Coffee Oyedele Adeyi Max Kotlyar Max Kotlyar Igor Jurisica Igor Jurisica Igor Jurisica Igor Jurisica Igor Jurisica
author_facet	Mamatha Bhat Mamatha Bhat Mamatha Bhat Mamatha Bhat Elisa Pasini Chiara Pastrello Chiara Pastrello Marc Angeli Cristina Baciu Mark Abovsky Mark Abovsky Angella Coffee Oyedele Adeyi Max Kotlyar Max Kotlyar Igor Jurisica Igor Jurisica Igor Jurisica Igor Jurisica Igor Jurisica
author_sort	Mamatha Bhat
title	Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis
title_short	Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis
title_full	Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis
title_fullStr	Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis
title_full_unstemmed	Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis
title_sort	estrogen receptor 1 inhibition of wnt/β-catenin signaling contributes to sex differences in hepatocarcinogenesis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/bcad94a7b6a3471bb30f1db3e5daad2f
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Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis

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