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

TitleMRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
Authors
KeywordsMRP4
Wnt/β-catenin
endometrium
embryo implantation
endometriosis
Issue Date2019
PublisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/
Citation
Theranostics, 2019, v. 9 n. 17, p. 5049-5064 How to Cite?
AbstractRationale: 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.
Persistent Identifierhttp://hdl.handle.net/10722/287757
ISSN
2019 Impact Factor: 8.579
2015 SCImago Journal Rankings: 2.702
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorChen, JJ-
dc.contributor.authorXiao, ZJ-
dc.contributor.authorMeng, X-
dc.contributor.authorWang, Y-
dc.contributor.authorYu, MK-
dc.contributor.authorHuang, WQ-
dc.contributor.authorSun, X-
dc.contributor.authorChen, H-
dc.contributor.authorDuan, YG-
dc.contributor.authorJiang, X-
dc.contributor.authorWong, MP-
dc.contributor.authorChan, HC-
dc.contributor.authorZou, F-
dc.contributor.authorRuan, YC-
dc.date.accessioned2020-10-05T12:02:49Z-
dc.date.available2020-10-05T12:02:49Z-
dc.date.issued2019-
dc.identifier.citationTheranostics, 2019, v. 9 n. 17, p. 5049-5064-
dc.identifier.issn1838-7640-
dc.identifier.urihttp://hdl.handle.net/10722/287757-
dc.description.abstractRationale: 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.-
dc.languageeng-
dc.publisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/-
dc.relation.ispartofTheranostics-
dc.rightsTheranostics. Copyright © Ivyspring International Publisher.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectMRP4-
dc.subjectWnt/β-catenin-
dc.subjectendometrium-
dc.subjectembryo implantation-
dc.subjectendometriosis-
dc.titleMRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer-
dc.typeArticle-
dc.identifier.emailXiao, ZJ: xiaozj@hku.hk-
dc.identifier.emailWong, MP: mwpik@hku.hk-
dc.identifier.authorityWong, MP=rp00348-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.7150/thno.32097-
dc.identifier.pmid31410201-
dc.identifier.pmcidPMC6691374-
dc.identifier.scopuseid_2-s2.0-85070483866-
dc.identifier.hkuros315165-
dc.identifier.volume9-
dc.identifier.issue17-
dc.identifier.spage5049-
dc.identifier.epage5064-
dc.publisher.placeAustralia-

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