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MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer

Rationale: Abnormal Wnt/β-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis. However, how Wnt/β-catenin signaling is regulated in the endometrium remains elusive. We explored...

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Autores principales: Chen, Jun-Jiang, Xiao, Zhi-Jie, Meng, Xiaojing, Wang, Yan, Yu, Mei Kuen, Huang, Wen Qing, Sun, Xiao, Chen, Hao, Duan, Yong-Gang, Jiang, Xiaohua, Wong, Maria Pik, Chan, Hsiao Chang, Zou, Fei, Ruan, Ye Chun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691374/
https://www.ncbi.nlm.nih.gov/pubmed/31410201
http://dx.doi.org/10.7150/thno.32097
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author Chen, Jun-Jiang
Xiao, Zhi-Jie
Meng, Xiaojing
Wang, Yan
Yu, Mei Kuen
Huang, Wen Qing
Sun, Xiao
Chen, Hao
Duan, Yong-Gang
Jiang, Xiaohua
Wong, Maria Pik
Chan, Hsiao Chang
Zou, Fei
Ruan, Ye Chun
author_facet Chen, Jun-Jiang
Xiao, Zhi-Jie
Meng, Xiaojing
Wang, Yan
Yu, Mei Kuen
Huang, Wen Qing
Sun, Xiao
Chen, Hao
Duan, Yong-Gang
Jiang, Xiaohua
Wong, Maria Pik
Chan, Hsiao Chang
Zou, Fei
Ruan, Ye Chun
author_sort Chen, Jun-Jiang
collection PubMed
description Rationale: Abnormal Wnt/β-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis. However, how Wnt/β-catenin signaling is regulated in the endometrium remains elusive. We explored possible regulation of Wnt/β-catenin signaling by multi-drug resistance protein 4 (MRP4), a potential target in cancer chemotherapy, and investigated the mechanism. Methods: Knockdown of MRP4 was performed in human endometrial cells in vitro or in a mouse embryo-implantation model in vivo. Immunoprecipitation, immunoblotting and immunofluorescence were used to assess protein interaction and stability. Wnt/β-catenin signaling was assessed by TOPflash reporter assay and quantitative PCR array. Normal and endometriotic human endometrial tissues were examined. Data from human microarray or RNAseq databases of more than 100 participants with endometriosis, endometrial cancer or IVF were analyzed. In vitro and in vivo tumorigenesis was performed. Results: MRP4-knockdown, but not its transporter-function-inhibition, accelerates β-catenin degradation in human endometrial cells. MRP4 and β-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium. MRP4-knockdown in mouse uterus reduces β-catenin levels, downregulates a series of Wnt/β-catenin target genes and impairs embryo implantation, which are all reversed by blocking β-catenin degradation. Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with β-catenin and Wnt/β-catenin target genes in the receptive endometrium in IVF, ectopic endometriotic lesions and endometrial cancers. Knockdown of MRP4 also inhibits in vitro and in vivo endometrial tumorigenesis. Conclusion: A previously undefined role of MRP4 in stabilizing β-catenin to sustain Wnt/β-catenin signaling in endometrial cells is revealed for both embryo implantation and endometrial disorders, suggesting MRP4 as a theranostic target for endometrial diseases associated with Wnt/β-catenin signaling abnormality.
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spelling pubmed-66913742019-08-13 MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer Chen, Jun-Jiang Xiao, Zhi-Jie Meng, Xiaojing Wang, Yan Yu, Mei Kuen Huang, Wen Qing Sun, Xiao Chen, Hao Duan, Yong-Gang Jiang, Xiaohua Wong, Maria Pik Chan, Hsiao Chang Zou, Fei Ruan, Ye Chun Theranostics Research Paper Rationale: Abnormal Wnt/β-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis. However, how Wnt/β-catenin signaling is regulated in the endometrium remains elusive. We explored possible regulation of Wnt/β-catenin signaling by multi-drug resistance protein 4 (MRP4), a potential target in cancer chemotherapy, and investigated the mechanism. Methods: Knockdown of MRP4 was performed in human endometrial cells in vitro or in a mouse embryo-implantation model in vivo. Immunoprecipitation, immunoblotting and immunofluorescence were used to assess protein interaction and stability. Wnt/β-catenin signaling was assessed by TOPflash reporter assay and quantitative PCR array. Normal and endometriotic human endometrial tissues were examined. Data from human microarray or RNAseq databases of more than 100 participants with endometriosis, endometrial cancer or IVF were analyzed. In vitro and in vivo tumorigenesis was performed. Results: MRP4-knockdown, but not its transporter-function-inhibition, accelerates β-catenin degradation in human endometrial cells. MRP4 and β-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium. MRP4-knockdown in mouse uterus reduces β-catenin levels, downregulates a series of Wnt/β-catenin target genes and impairs embryo implantation, which are all reversed by blocking β-catenin degradation. Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with β-catenin and Wnt/β-catenin target genes in the receptive endometrium in IVF, ectopic endometriotic lesions and endometrial cancers. Knockdown of MRP4 also inhibits in vitro and in vivo endometrial tumorigenesis. Conclusion: A previously undefined role of MRP4 in stabilizing β-catenin to sustain Wnt/β-catenin signaling in endometrial cells is revealed for both embryo implantation and endometrial disorders, suggesting MRP4 as a theranostic target for endometrial diseases associated with Wnt/β-catenin signaling abnormality. Ivyspring International Publisher 2019-07-09 /pmc/articles/PMC6691374/ /pubmed/31410201 http://dx.doi.org/10.7150/thno.32097 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Chen, Jun-Jiang
Xiao, Zhi-Jie
Meng, Xiaojing
Wang, Yan
Yu, Mei Kuen
Huang, Wen Qing
Sun, Xiao
Chen, Hao
Duan, Yong-Gang
Jiang, Xiaohua
Wong, Maria Pik
Chan, Hsiao Chang
Zou, Fei
Ruan, Ye Chun
MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
title MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
title_full MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
title_fullStr MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
title_full_unstemmed MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
title_short MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
title_sort mrp4 sustains wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691374/
https://www.ncbi.nlm.nih.gov/pubmed/31410201
http://dx.doi.org/10.7150/thno.32097
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