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GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells
Women consistently show lower incidence and mortality rates for colorectal cancer (CRC) compared to men. Epidemiological evidence supports a pivotal role for estrogen in protecting women against CRC. Estrogen protective effects in CRC have been mainly attributed to the estrogen receptor beta (ERβ) h...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9603962/ https://www.ncbi.nlm.nih.gov/pubmed/36293473 http://dx.doi.org/10.3390/ijms232012581 |
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author | Abancens, Maria Harvey, Brian J. McBryan, Jean |
author_facet | Abancens, Maria Harvey, Brian J. McBryan, Jean |
author_sort | Abancens, Maria |
collection | PubMed |
description | Women consistently show lower incidence and mortality rates for colorectal cancer (CRC) compared to men. Epidemiological evidence supports a pivotal role for estrogen in protecting women against CRC. Estrogen protective effects in CRC have been mainly attributed to the estrogen receptor beta (ERβ) however its expression is lost during CRC progression. The role of the G-protein coupled membrane estrogen receptor (GPER/GPER1/GPR30), which remains expressed after ERβ loss in CRC, is currently under debate. We hypothesise that estrogen can protect against CRC progression via GPER by modulating the Wnt/β-catenin proliferative pathway which is commonly hyperactivated in CRC. We sought evidence of sexual dimorphism within the Wnt/β-catenin pathway by conducting Kaplan–Meier analyses based on gene expression of the Wnt receptor FZD1 (Frizzled 1) in multiple public domain CRC patient data sets. High expression of FZD1 was associated with poor relapse-free survival rates in the male but not the female population. In female-derived HT29 CRC cell lines, we show that β-catenin nuclear translocation was not affected by treatment with the GPER agonist G1. However, G1 prevented the Wnt pathway-induced upregulation of the JUN oncogene. These novel findings indicate a mechanistic role for GPER in protecting against CRC progression by selectively reducing the tumorigenic effects of hyperactive Wnt/β-catenin signalling pathways in CRC. |
format | Online Article Text |
id | pubmed-9603962 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96039622022-10-27 GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells Abancens, Maria Harvey, Brian J. McBryan, Jean Int J Mol Sci Article Women consistently show lower incidence and mortality rates for colorectal cancer (CRC) compared to men. Epidemiological evidence supports a pivotal role for estrogen in protecting women against CRC. Estrogen protective effects in CRC have been mainly attributed to the estrogen receptor beta (ERβ) however its expression is lost during CRC progression. The role of the G-protein coupled membrane estrogen receptor (GPER/GPER1/GPR30), which remains expressed after ERβ loss in CRC, is currently under debate. We hypothesise that estrogen can protect against CRC progression via GPER by modulating the Wnt/β-catenin proliferative pathway which is commonly hyperactivated in CRC. We sought evidence of sexual dimorphism within the Wnt/β-catenin pathway by conducting Kaplan–Meier analyses based on gene expression of the Wnt receptor FZD1 (Frizzled 1) in multiple public domain CRC patient data sets. High expression of FZD1 was associated with poor relapse-free survival rates in the male but not the female population. In female-derived HT29 CRC cell lines, we show that β-catenin nuclear translocation was not affected by treatment with the GPER agonist G1. However, G1 prevented the Wnt pathway-induced upregulation of the JUN oncogene. These novel findings indicate a mechanistic role for GPER in protecting against CRC progression by selectively reducing the tumorigenic effects of hyperactive Wnt/β-catenin signalling pathways in CRC. MDPI 2022-10-20 /pmc/articles/PMC9603962/ /pubmed/36293473 http://dx.doi.org/10.3390/ijms232012581 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Abancens, Maria Harvey, Brian J. McBryan, Jean GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells |
title | GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells |
title_full | GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells |
title_fullStr | GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells |
title_full_unstemmed | GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells |
title_short | GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells |
title_sort | gper agonist g1 prevents wnt-induced jun upregulation in ht29 colorectal cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9603962/ https://www.ncbi.nlm.nih.gov/pubmed/36293473 http://dx.doi.org/10.3390/ijms232012581 |
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