Theranostics 2019; 9(17):5049-5064. doi:10.7150/thno.32097 This issue Cite

Research Paper

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

Jun-Jiang Chen1,2,3,4*, Zhi-Jie Xiao5*, Xiaojing Meng1, Yan Wang3, Mei Kuen Yu2,3, Wen Qing Huang3, Xiao Sun3, Hao Chen3,6, Yong-Gang Duan7, Xiaohua Jiang3, Maria Pik Wong5, Hsiao Chang Chan3, Fei Zou1✉, Ye Chun Ruan2✉

1. Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
2. Deparment of Biomedical Engineering, Faculty of Engineering, the Hong Kong Polytechnic University.
3. Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.
4. Department of Physiology, School of Medicine, Jinan University, Guangzhou, China
5. Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
6. Department of Gynecology, Shenzhen Second People's Hospital, 518035 Shenzhen, China.
7. Centre of Reproductive Medicine and Andrology, Shenzhen Second People's Hospital, 518035 Shenzhen, China.
*These authors contributed equally to this work

Citation:
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. doi:10.7150/thno.32097. https://www.thno.org/v09p5049.htm
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Abstract

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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.

Keywords: MRP4, Wnt/β-catenin, endometrium, embryo implantation, endometriosis, endometrial cancer.


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APA
Chen, J.J., Xiao, Z.J., Meng, X., Wang, Y., Yu, M.K., Huang, W.Q., Sun, X., Chen, H., Duan, Y.G., Jiang, X., Wong, M.P., Chan, H.C., Zou, F., Ruan, Y.C. (2019). MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer. Theranostics, 9(17), 5049-5064. https://doi.org/10.7150/thno.32097.

ACS
Chen, J.J.; Xiao, Z.J.; Meng, X.; Wang, Y.; Yu, M.K.; Huang, W.Q.; Sun, X.; Chen, H.; Duan, Y.G.; Jiang, X.; Wong, M.P.; Chan, H.C.; Zou, F.; Ruan, Y.C. MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer. Theranostics 2019, 9 (17), 5049-5064. DOI: 10.7150/thno.32097.

NLM
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. doi:10.7150/thno.32097. https://www.thno.org/v09p5049.htm

CSE
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. 2019. MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer. Theranostics. 9(17):5049-5064.

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