Estrogen and ERα enhanced β‐catenin degradation and suppressed its downstream target genes to block the metastatic function of HA22T hepatocellular carcinoma cells via modulating GSK‐3β and β‐TrCP expression

Abstract

In our previous experiments, we found β-catenin was highly expressed in the tumor area with high invasive ability and poor prognosis. In this study, we have examined the mechanism by which ERα regulates β-catenin expression as well as the metastasis ability of hepatocellular cancer HA22T cells. To identify whether the anticancer effect of estrogen and ERα is mediated through suppression of β-catenin expression, we co-transfected pCMV-β-catenin and ERα into HA22T cells, and determined the cell motility by wound healing, invasion, and migration assays. Results showed that estrogen and/or ERα inhibited β-catenin gene expression and repressed HA22T cell motility demonstrated that similar data was observed in cells expressing the ERα stable clone. Moreover, we examined the protein-protein interaction between ERα and β-catenin by immunostain, co-immunoprecipitation, and Western blotting. E2 enhanced the binding of ERα with β-catenin and then triggered β-catenin to bind with E3 ligase (βTrCP) to promote β-catenin degradation. Finally by employing systematic ChIP studies, we showed ERα can interact directly with the β-catenin promoter region following E2 treatment. All our results reveal that estrogen and ERα blocked metastatic function of HA22T cells by modulating GSK3β and βTrCP expression and further enhanced β-catenin degradation and suppressed its downstream target genes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 519-529, 2017.

Molecular characterization of lysyl oxidase‐mediated extracellular matrix remodeling during mouse decidualization

“…The ERa is mainly activated by estrogen to regulate a wide range of cellular activities in response to estrogen [20]. Recent studies have shown that in HA22T cells, ERa binds to GSk-3b and induced ubiquitination and degradation of b-catenin in a ligand-dependent manner [21,22]. Our studies show that GSK-3b and c-MYC can be induced by estrogen in ovariectomized mouse while estrogen can reduce nuclear b-catenin expression.…”

<p>Wntless (Wls): A Prognostic Index for Progression and Patient Survival of Breast Cancer</p>

“…The binding of ERα with β-catenin was enhanced by estrogen, which activated the binding of β-catenin with E3 ligase to promote its degradation and block the metastasis in HCC cells. 24 Considering that liver cancer is more prevalent in males, the possible mechanism associated with a negative correlation between Wls and ER-negative breast cancer still needs to be further investigated.…”

Therapeutic Value of Estrogen Receptor α in Hepatocellular Carcinoma Based on Molecular Mechanisms

“…[9][10][11][12] Moreover, a multitude of studies have shown that the expression of ERα in primary HCC tissues is decreased compared to normal liver tissues or the adjacent tissues, which indirectly confirmed the suppressive effects of ERα in HCC. [13][14][15] In light of this anti-tumor effect of ERα in HCC, reactivating ERα signaling can offer a new therapeutic strategy in HCC prevention and treatment.…”