MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
Identifieur interne : 000664 ( Main/Merge ); précédent : 000663; suivant : 000665MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
Auteurs : Jun-Jiang Chen [République populaire de Chine] ; Zhi-Jie Xiao [Hong Kong] ; Xiaojing Meng [République populaire de Chine] ; Yan Wang ; Mei Kuen Yu ; Wen Qing Huang ; Xiao Sun ; Hao Chen [République populaire de Chine] ; Yong-Gang Duan [République populaire de Chine] ; Xiaohua Jiang ; Maria Pik Wong [Hong Kong] ; Hsiao Chang Chan ; Fei Zou [République populaire de Chine] ; Ye Chun RuanSource :
- Theranostics [ 1838-7640 ] ; 2019.
Abstract
Url:
DOI: 10.7150/thno.32097
PubMed: 31410201
PubMed Central: 6691374
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<affiliation wicri:level="1"><nlm:aff id="A6">Department of Gynecology, Shenzhen Second People's Hospital, 518035 Shenzhen, China.</nlm:aff>
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<author><name sortKey="Wong, Maria Pik" sort="Wong, Maria Pik" uniqKey="Wong M" first="Maria Pik" last="Wong">Maria Pik Wong</name>
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<author><name sortKey="Ruan, Ye Chun" sort="Ruan, Ye Chun" uniqKey="Ruan Y" first="Ye Chun" last="Ruan">Ye Chun Ruan</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer</title>
<author><name sortKey="Chen, Jun Jiang" sort="Chen, Jun Jiang" uniqKey="Chen J" first="Jun-Jiang" last="Chen">Jun-Jiang Chen</name>
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<country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country>
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<affiliation><nlm:aff id="A2">Deparment of Biomedical Engineering, Faculty of Engineering, the Hong Kong Polytechnic University.</nlm:aff>
<wicri:noCountry code="subfield">the Hong Kong Polytechnic University.</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A4">Department of Physiology, School of Medicine, Jinan University, Guangzhou, China</nlm:aff>
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<wicri:regionArea>Department of Physiology, School of Medicine, Jinan University, Guangzhou</wicri:regionArea>
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<author><name sortKey="Xiao, Zhi Jie" sort="Xiao, Zhi Jie" uniqKey="Xiao Z" first="Zhi-Jie" last="Xiao">Zhi-Jie Xiao</name>
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<author><name sortKey="Meng, Xiaojing" sort="Meng, Xiaojing" uniqKey="Meng X" first="Xiaojing" last="Meng">Xiaojing Meng</name>
<affiliation wicri:level="3"><nlm:aff id="A1">Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country>
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<placeName><settlement type="city">Jiangmen</settlement>
<region type="province">Guangdong</region>
</placeName>
</affiliation>
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<author><name sortKey="Wang, Yan" sort="Wang, Yan" uniqKey="Wang Y" first="Yan" last="Wang">Yan Wang</name>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Yu, Mei Kuen" sort="Yu, Mei Kuen" uniqKey="Yu M" first="Mei Kuen" last="Yu">Mei Kuen Yu</name>
<affiliation><nlm:aff id="A2">Deparment of Biomedical Engineering, Faculty of Engineering, the Hong Kong Polytechnic University.</nlm:aff>
<wicri:noCountry code="subfield">the Hong Kong Polytechnic University.</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Huang, Wen Qing" sort="Huang, Wen Qing" uniqKey="Huang W" first="Wen Qing" last="Huang">Wen Qing Huang</name>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Sun, Xiao" sort="Sun, Xiao" uniqKey="Sun X" first="Xiao" last="Sun">Xiao Sun</name>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Chen, Hao" sort="Chen, Hao" uniqKey="Chen H" first="Hao" last="Chen">Hao Chen</name>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A6">Department of Gynecology, Shenzhen Second People's Hospital, 518035 Shenzhen, China.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country>
<wicri:regionArea>Department of Gynecology, Shenzhen Second People's Hospital, 518035 Shenzhen</wicri:regionArea>
<placeName><settlement type="city">Shenzhen</settlement>
<region type="province">Guangdong</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Duan, Yong Gang" sort="Duan, Yong Gang" uniqKey="Duan Y" first="Yong-Gang" last="Duan">Yong-Gang Duan</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Centre of Reproductive Medicine and Andrology, Shenzhen Second People's Hospital, 518035 Shenzhen, China.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country>
<wicri:regionArea>Centre of Reproductive Medicine and Andrology, Shenzhen Second People's Hospital, 518035 Shenzhen</wicri:regionArea>
<placeName><settlement type="city">Shenzhen</settlement>
<region type="province">Guangdong</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jiang, Xiaohua" sort="Jiang, Xiaohua" uniqKey="Jiang X" first="Xiaohua" last="Jiang">Xiaohua Jiang</name>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wong, Maria Pik" sort="Wong, Maria Pik" uniqKey="Wong M" first="Maria Pik" last="Wong">Maria Pik Wong</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong</nlm:aff>
<country xml:lang="fr">Hong Kong</country>
<wicri:regionArea>Department of Pathology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chan, Hsiao Chang" sort="Chan, Hsiao Chang" uniqKey="Chan H" first="Hsiao Chang" last="Chan">Hsiao Chang Chan</name>
<affiliation><nlm:aff id="A3">Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</nlm:aff>
<wicri:noCountry code="subfield">the Chinese University of Hong Kong.</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zou, Fei" sort="Zou, Fei" uniqKey="Zou F" first="Fei" last="Zou">Fei Zou</name>
<affiliation wicri:level="3"><nlm:aff id="A1">Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country>
<wicri:regionArea>Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou</wicri:regionArea>
<placeName><settlement type="city">Jiangmen</settlement>
<region type="province">Guangdong</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ruan, Ye Chun" sort="Ruan, Ye Chun" uniqKey="Ruan Y" first="Ye Chun" last="Ruan">Ye Chun Ruan</name>
<affiliation><nlm:aff id="A2">Deparment of Biomedical Engineering, Faculty of Engineering, the Hong Kong Polytechnic University.</nlm:aff>
<wicri:noCountry code="subfield">the Hong Kong Polytechnic University.</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Theranostics</title>
<idno type="eISSN">1838-7640</idno>
<imprint><date when="2019">2019</date>
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<front><div type="abstract" xml:lang="en"><p><bold>Rationale</bold>
: 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.</p>
<p><bold>Methods</bold>
: Knockdown of MRP4 was performed in human endometrial cells <italic>in vitro</italic>
or in a mouse embryo-implantation model <italic>in vivo</italic>
. 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. <italic>In vitro</italic>
and <italic>in vivo</italic>
tumorigenesis was performed.</p>
<p><bold>Results</bold>
: 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 <italic>in vitro</italic>
and <italic>in vivo</italic>
endometrial tumorigenesis.</p>
<p><bold>Conclusion</bold>
: 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.</p>
</div>
</front>
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