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

Abstract

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.

Systems Pharmacology-Based Strategy to Investigate the Mechanism of Ruangan Lidan Decoction for Treatment of Hepatocellular Carcinoma

“…CALM1 gene decreases gradually with tumor enlargement and is also a potential biomarker for the diagnosis of HCC [ 50 ]. Moreover, high expression of ESR1 has a protective effect on the overall survival of HCC and is associated with a favorable prognosis [ 51 , 52 ].…”

Transcription factors-related molecular subtypes and risk prognostic model: exploring the immunogenicity landscape and potential drug targets in hepatocellular carcinoma

“…8 ). ESR1 was expressed at lower levels in HCC tissues than in normal tissues and correlated with poorer prognosis in HCC patients [ 19 , 20 ]. The downregulation of ESR1 may be related to the carcinogenic driving force of HCC.…”

Stearoyl-CoA Desaturases1 Accelerates Non-Small Cell Lung Cancer Metastasis by Promoting Aromatase Expression to Improve Estrogen Synthesis

“…Estrogen receptor-mediated signaling pathways are important in tumor pathogenesis. The crosstalk between the estrogen signaling pathway and Wnt/β-catenin is controversial [ 40 , 41 , 42 ]. The activation of ER-α inhibits the Wnt/β-catenin pathway and the transcription of its downstream target genes, c-Myc and Cyclin D1, in hepatocarcinogenesis [ 42 ].…”

“…The crosstalk between the estrogen signaling pathway and Wnt/β-catenin is controversial [ 40 , 41 , 42 ]. The activation of ER-α inhibits the Wnt/β-catenin pathway and the transcription of its downstream target genes, c-Myc and Cyclin D1, in hepatocarcinogenesis [ 42 ]. Estrogen induces Wnt-activated self-renewal of breast cancer stem cells via Erα [ 41 ].…”