Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/81297
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Title: MRP4 sustains Wnt/beta-catenin signaling for pregnancy, endometriosis and endometrial cancer
Authors: Chen, JJ 
Xiao, ZJ
Meng, XJ
Wang, Y
Yu, MK
Huang, WQ
Sun, X
Chen, H
Duan, YG
Jiang, XH
Wong, MP
Chan, HC
Zou, F
Ruan, YC 
Issue Date: 2019
Source: Theranostics, 2019, v. 9, no. 17, p. 5049-5064
Abstract: Rationale: Abnormal Wnt/beta-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/beta-catenin signaling is regulated in the endometrium remains elusive. We explored possible regulation of Wnt/beta-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/beta-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 beta-catenin degradation in human endometrial cells. MRP4 and beta-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium. MRP4-knockdown in mouse uterus reduces beta-catenin levels, downregulates a series of Wnt/beta-catenin target genes and impairs embryo implantation, which are all reversed by blocking beta-catenin degradation. Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with beta-catenin and Wnt/beta-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 beta-catenin to sustain Wnt/beta-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/beta-catenin signaling abnormality.
Keywords: MRP4
Wnt/beta-catenin
Endometrium
Embryo implantation
Endometriosis
Endometrial cancer
Publisher: Ivyspring International Publisher
Journal: Theranostics 
EISSN: 1838-7640
DOI: 10.7150/thno.32097
Rights: © 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.
The following publication Chen JJ, Xiao ZJ, Meng X, Wang Y, Yu MK, Huang WQ, Sun X, Chen H, Duan YG, Jiang X, Wong MP, Chan HC, Zou F, Ruan YC. MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer. Theranostics 2019; 9(17):5049-5064 is available at https://dx.doi.org/10.7150/thno.32097
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