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

被引:21
作者
Bhat, Mamatha [1 ,2 ,3 ,4 ]
Pasini, Elisa [1 ]
Pastrello, Chiara [5 ,6 ]
Angeli, Marc [1 ]
Baciu, Cristina [1 ]
Abovsky, Mark [5 ,6 ]
Coffee, Angella [7 ,8 ]
Adeyi, Oyedele [7 ,8 ]
Kotlyar, Max [5 ,6 ]
Jurisica, Igor [5 ,6 ,9 ,10 ,11 ]
机构
[1] Univ Hlth Network, Ajmera Transplant Program, Toronto, ON, Canada
[2] Univ Toronto, Div Gastroenterol & Hepatol, Toronto, ON, Canada
[3] Univ Toronto, Inst Med Sci, Toronto, ON, Canada
[4] Univ Hlth Network, Toronto Gen Hosp Res Inst, Toronto, ON, Canada
[5] Univ Hlth Network, Schroeder Arthrit Inst, Div Orthoped Surg, Osteoarthritis Res Program, Toronto, ON, Canada
[6] Univ Hlth Network, Krembil Res Inst, Toronto, ON, Canada
[7] Univ Minnesota, Dept Pathol, Minneapolis, MN 55455 USA
[8] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA
[9] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[10] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada
[11] Slovak Acad Sci, Inst Neuroimmunol, Bratislava, Slovakia
基金
加拿大创新基金会;
关键词
estrogen; hepatocellular carcinoma; high-throughput; network analysis; Wnt; b-catenin; ESR1; interactome; PPIs; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; ANDROGEN RECEPTOR; BETA-AGONISTS; LIVER-CANCER; TUMOR; PROTEIN; BREAST; ALPHA; SURVIVAL;
D O I
10.3389/fonc.2021.777834
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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/beta-catenin signaling pathway. ER-alpha (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/beta-Catenin signaling. In vitro experiments confirmed colocalization of beta-catenin with ER-alpha, leading to inhibition of beta-catenin-mediated transcription of target genes c-Myc and Cyclin D1. ConclusionCombined, the centrality of ESR1 and its inhibition of the Wnt/beta-catenin signaling axis provide a biological rationale for protection against HCC incidence and progression in women.
引用
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页数:12
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