MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
Identifieur interne : 000614 ( Pmc/Checkpoint ); précédent : 000613; suivant : 000615MRP4 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
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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><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><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><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Physiology, School of Medicine, Jinan University, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Xiao, Zhi Jie" sort="Xiao, Zhi Jie" uniqKey="Xiao Z" first="Zhi-Jie" last="Xiao">Zhi-Jie Xiao</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="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><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="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></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31410201</idno><idno type="pmc">6691374</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691374</idno><idno type="RBID">PMC:6691374</idno><idno type="doi">10.7150/thno.32097</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000821</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000821</idno><idno type="wicri:Area/Pmc/Curation">000821</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000821</idno><idno type="wicri:Area/Pmc/Checkpoint">000614</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000614</idno></publicationStmt><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><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><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><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Physiology, School of Medicine, Jinan University, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Xiao, Zhi Jie" sort="Xiao, Zhi Jie" uniqKey="Xiao Z" first="Zhi-Jie" last="Xiao">Zhi-Jie Xiao</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="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><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="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></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cha, J" uniqKey="Cha J">J Cha</name></author><author><name sortKey="Sun, X" uniqKey="Sun X">X Sun</name></author><author><name sortKey="Dey, Sk" uniqKey="Dey S">SK Dey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Revel, A" uniqKey="Revel A">A Revel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ruan, Yc" uniqKey="Ruan Y">YC Ruan</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Chan, Hc" uniqKey="Chan H">HC Chan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bulun, Se" uniqKey="Bulun S">SE Bulun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cramer, Dw" uniqKey="Cramer D">DW Cramer</name></author><author><name sortKey="Missmer, Sa" uniqKey="Missmer S">SA Missmer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Murray, Mj" uniqKey="Murray M">MJ Murray</name></author><author><name sortKey="Lessey, Ba" uniqKey="Lessey B">BA Lessey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mohamed, Oa" uniqKey="Mohamed O">OA Mohamed</name></author><author><name sortKey="Jonnaert, M" uniqKey="Jonnaert M">M Jonnaert</name></author><author><name sortKey="Labelle Dumais, C" uniqKey="Labelle Dumais C">C Labelle-Dumais</name></author><author><name sortKey="Kuroda, K" uniqKey="Kuroda K">K Kuroda</name></author><author><name sortKey="Clarke, Hj" uniqKey="Clarke H">HJ Clarke</name></author><author><name sortKey="Dufort, D" uniqKey="Dufort D">D Dufort</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jha, Rk" uniqKey="Jha R">RK Jha</name></author><author><name sortKey="Titus, S" uniqKey="Titus S">S Titus</name></author><author><name sortKey="Saxena, D" uniqKey="Saxena D">D Saxena</name></author><author><name sortKey="Kumar, Pg" uniqKey="Kumar P">PG Kumar</name></author><author><name sortKey="Laloraya, M" uniqKey="Laloraya M">M Laloraya</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herington, Jl" uniqKey="Herington J">JL Herington</name></author><author><name sortKey="Bi, J" uniqKey="Bi J">J Bi</name></author><author><name sortKey="Martin, Jd" uniqKey="Martin J">JD Martin</name></author><author><name sortKey="Bany, Bm" uniqKey="Bany B">BM 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Theranostics</journal-id><journal-id journal-id-type="iso-abbrev">Theranostics</journal-id><journal-id journal-id-type="publisher-id">thno</journal-id><journal-title-group><journal-title>Theranostics</journal-title></journal-title-group><issn pub-type="epub">1838-7640</issn><publisher><publisher-name>Ivyspring International Publisher</publisher-name><publisher-loc>Sydney</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31410201</article-id><article-id pub-id-type="pmc">6691374</article-id><article-id pub-id-type="doi">10.7150/thno.32097</article-id><article-id pub-id-type="publisher-id">thnov09p5049</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Jun-Jiang</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A4">4</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Xiao</surname><given-names>Zhi-Jie</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Meng</surname><given-names>Xiaojing</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Yu</surname><given-names>Mei Kuen</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Wen Qing</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Xiao</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Hao</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Duan</surname><given-names>Yong-Gang</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Xiaohua</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Maria Pik</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Chan</surname><given-names>Hsiao Chang</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Zou</surname><given-names>Fei</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Ruan</surname><given-names>Ye Chun</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.</aff><aff id="A2"><label>2</label>Deparment of Biomedical Engineering, Faculty of Engineering, the Hong Kong Polytechnic University.</aff><aff id="A3"><label>3</label>Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong.</aff><aff id="A4"><label>4</label>Department of Physiology, School of Medicine, Jinan University, Guangzhou, China</aff><aff id="A5"><label>5</label>Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong</aff><aff id="A6"><label>6</label>Department of Gynecology, Shenzhen Second People's Hospital, 518035 Shenzhen, China.</aff><aff id="A7"><label>7</label>Centre of Reproductive Medicine and Andrology, Shenzhen Second People's Hospital, 518035 Shenzhen, China.</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding authors: <email>sharon.yc.ruan@polyu.edu.hk</email> (Y.C.R.) or <email>zfei@smu.edu.cn</email> (F.Z.)</corresp><fn fn-type="equal" id="FNA_star"><p>*These authors contributed equally to this work</p></fn><fn fn-type="COI-statement"><p>Competing Interests: The authors have declared that no competing interest exists.</p></fn></author-notes><pub-date pub-type="collection"><year>2019</year></pub-date><pub-date pub-type="epub"><day>9</day><month>7</month><year>2019</year></pub-date><volume>9</volume><issue>17</issue><fpage>5049</fpage><lpage>5064</lpage><history><date date-type="received"><day>8</day><month>12</month><year>2018</year></date><date date-type="accepted"><day>8</day><month>5</month><year>2019</year></date></history><permissions><copyright-statement>© The author(s)</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>). See <ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link> for full terms and conditions.</license-p></license></permissions><abstract><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></abstract><kwd-group><kwd>MRP4</kwd><kwd>Wnt/β-catenin</kwd><kwd>endometrium</kwd><kwd>embryo implantation</kwd><kwd>endometriosis</kwd><kwd>endometrial cancer.</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold> MRP4 sustains Wnt/β-catenin signaling independent of transporting PGE<sub>2</sub> in human endometrial epithelial cells. A)</bold> Representative western blots with quantification for MRP4 and active β-catenin in human endometrial epithelial cells (ISK) treated with siRNAs against MRP4 (siMRP4) or non-silencing controls (siNC), in the presence (+) or absence (-) of Wnt3a (100 ng/ml). β-tubulin was used as the loading control. n = 6. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, by Student's <italic>t</italic> test. <bold>B)</bold> ELISA detection of PGE<sub>2</sub> levels in culture medium of ISK cells incubated with or without (Ctrl) MK-571 (10 μM, a blocker of MRP4 transporter function). n = 4. **<italic>P</italic> < 0.01, by Student's <italic>t</italic> test. <bold>C-D)</bold> Representative western blots with quantification for active β-catenin in ISK cells incubated with MK-571 (10 µM, C) or PGE<sub>2</sub> (10 µM, D) for 0-24 h. GAPDH was used as the loading control. n = 4. ns: not significant with <italic>P</italic> > 0.05, by Student's <italic>t</italic> test. <bold>E-G)</bold> Measurement of luciferase activity in TOPflash (β-catenin/TCF reporter)-transfected ISK cells treated with shRNAs (E, n = 3) against MRP4 (shMRP4) or non-silencing controls (shNC), or, incubated with or without (Ctrl) MK-571 (10 µM, F, n = 4) or PGE<sub>2</sub> (10 µM, G, n = 4). ***<italic>P</italic> < 0.001, ns: not significant with <italic>P</italic> > 0.05, by Student's <italic>t</italic> test.</p></caption><graphic xlink:href="thnov09p5049g001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold> MRP4 stabilizes β-catenin in human endometrial epithelial cells. A)</bold> Representative western blots for MRP4 and β-catenin in ISK cells before (Total lysate) and after immuno-precipitated (IP) for β-catenin or IgG as the IP control. n = 3. <bold>B)</bold> Representative western blots with quantification for MRP4, active (non-phosphorylated), degrading (phosphorylated, p-β-catenin) and total (phosphorylated and non-phosphorylated) β-catenin in siNC- or siMPR4-transfected ISK cells incubated with cycloheximide (CHX, 10 μM, a protein synthesis inhibitor) for 0-8 h. β-actin or β-tubulin was used as the loading control. n = 3. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001, by two-way ANOVA. <bold>C)</bold> Representative western blots with quantification for MRP4 and active β-catenin in ISK cells transfected with siMRP4 or siNC, in the presence (+) or absence (-) of MG132 (10 μM, a proteasome inhibitor) or Chloroquine (10 μM, a lysosome inhibitor). β-actin was used as the loading control. n = 3. ***<italic>P</italic> < 0.001, ns: not significant with <italic>P</italic> > 0.05, by Student's <italic>t</italic> test. <bold>D)</bold> Representative western blots with quantification for active β-catenin and p-β-catenin in ISK cells transfected with siNC or siMRP4, in the presence (+) or absence (-) of CHIR-99021 (CHIR, 10 µM, an inhibitor of glycogen synthase kinase-3β blocking degradation-associated phosphorylation of β-catenin). β-tubulin was used as the loading control. n = 5. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ns: not significant with <italic>P</italic> > 0.05, by Student's <italic>t</italic> test. <bold>E)</bold> Measurement of luciferase activity in TOPflash-transfected ISK cells treated with shMRP4 or shNC, in the presence of CHIR (10 µM) or DMSO as the control, n = 4. **<italic>P</italic> < 0.01, ns: not significant with <italic>P</italic> > 0.05, by Student's <italic>t</italic> test.</p></caption><graphic xlink:href="thnov09p5049g002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><bold> MRP4 interacts with β-catenin in the endometrium required for embryo implantation in mice. A)</bold> Confocal images of immunofluorescence labelling for MRP4 (red) and β-catenin (green) in mouse endometrium at 5 d.p.c. (days post coitum). Scale bars = 5 μm.<bold> B)</bold> Representative western blots for MRP4 and β-catenin in protein extracts from mouse uterine tissues (48 h after intrauterinally injected with siMRP4 or siNC, 100 pmole per uterine horn), before (Total lysate) and after immuno-precipitated (IP) for β-catenin or IgG as the IP control. n = 3.<bold> C-D)</bold> Quantitative PCR (qPCR) analysis (C, 4 d.p.c.) of and immunofluorescence staining (D, 5 d.p.c.) for MRP4 in mouse uteri treated with siMRP4 or siNC (100 pmole per uterine horn). n = 3. ***<italic>P</italic> < 0.001, by Student's <italic>t</italic> test. Scale bars in D = 5 µm. <bold>E)</bold> Implanted embryo numbers counted at 7 d.p.c. in uteri treated with siNC or siMRP4 (50-100 pmole per uterine horn). <italic>Right</italic>: Representative photograph of a mouse uterus injected with siMRP4 (100 pmole, right horn) or siNC (100 pmole, left horn) with arrows indicating implantation sites. n = 4-7. **<italic>P</italic> < 0.01, by Student's <italic>t</italic> test. <bold>F-G)</bold> Representative images of hematoxylin & eosin staining (F, 5 d.p.c, n = 4 mice) and qPCR analysis of <italic>Hoxa10</italic>,<italic> Igf2, Lif</italic>,<italic> Pparg</italic> (G, 5 d.p.c, n = 3-5) in mouse uteri treated with siMRP4 or siNC (100 pmole per uterine horn). *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, by Student's <italic>t</italic> test. Scale bars in F = 50 μm.</p></caption><graphic xlink:href="thnov09p5049g003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p><bold> MRP4 sustains Wnt/β-catenin signaling in the endometrium for embryo implantation in mice. A)</bold> qPCR array showing downregulation of Wnt/β-catenin target genes in the mouse uterine horns (5 d.p.c) with MRP4 knockdown by siMRP4 (100 pmole per uterine horn), as compared to the paired uterine horns treated with siNC (100 pmole per uterine horn). Data are percentages of reduction in mRNA level of genes, (siMRP4-siNC) / siNC %. n = 3. <italic>P</italic> values are *(< 0.05), **(< 0.01), ***(< 0.001), or as indicated, by paired Student's <italic>t</italic> test. <bold>B-C)</bold> Representative western blots with quantification for active β-catenin (B) and immunofluorescence staining for total β-catenin (C) in mouse uteri (5 d.p.c.) injected with siNC or siMRP4 (100 pmole per uterine horn) and co-treated with CHIR (10 µM) or DMSO as the control. n = 3. **<italic>P</italic> < 0.01, ns: not significant with <italic>P</italic> > 0.05, by Student's <italic>t</italic> test. Scale bars in C = 10 µm. <bold>D)</bold> Representative images of hematoxylin & eosin staining in mouse uteri (5 d.p.c) with MRP4 knockdown (siMRP4) and treatment with DMSO or CHIR (10 µM). n = 4. Scale bars = 50 μm. <bold>E)</bold> qPCR analysis of <italic>Igf2, Lif</italic> and <italic>Pparg</italic> at 5 d.p.c. in mouse uteri injected with siNC or siMRP4 (100 pmole per uterine horn), and co-treated with CHIR (10 µM) or DMSO as the control. n = 3-5, *<italic>P</italic> < 0.05, by Student's <italic>t</italic> test. <bold>F)</bold> Implanted embryo numbers counted at 7 d.p.c. in mouse uteri injected with siNC or siMRP4 (100 pmole per uterine horn), and co-treated with CHIR (10-100 µM) or DMSO as the control. n = 6-7, *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, by One-way ANOVA.</p></caption><graphic xlink:href="thnov09p5049g004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p><bold> MRP4 interacts with β-catenin and correlates with Wnt/β-catenin signaling genes in human endometrium. A)</bold> Confocal images of immunofluorescence labelling for MRP4 (red) and β-catenin (green) in normal human endometrial tissues. Scale bars = 10 μm. <bold>B)</bold> Correlation analysis of mRNA levels of MRP4 and β-catenin or Wnt/β-catenin targeting genes (i.e. <italic>Birc5, Bmp4, Ccnd1, Gdf5, Id2, Igf1, Il6, Nrp1</italic> and<italic> Twist1</italic>) in human endometrial tissues collected at mid-secretory phase during IVF treatment (n = 115). Data were retrieved from a previously published dataset (GSE58144, <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/geo">http://www.ncbi.nlm.nih.gov/geo</ext-link>). Values of <italic>r</italic> and <italic>P</italic> are shown for each analysis by Pearson correlation test.</p></caption><graphic xlink:href="thnov09p5049g005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p><bold>MRP4 correlates with β-catenin in human endometriosis and endometrial cancer. A)</bold> Western blots for MRP4, active β-catenin and β-catenin, with correlation tests of their quantified protein levels in human endometriotic samples (n = 19). β-actin was used as the loading control. Values of <italic>r</italic> and <italic>P</italic> are shown for each analysis by Pearson correlation test. <bold>B)</bold> Correlation analysis of MRP4 and β-catenin mRNA levels in human endometrial cancer (dataset ID: UCEC from TCGA Research Network: <ext-link ext-link-type="uri" xlink:href="http://cancergenome.nih.gov/">http://cancergenome.nih.gov/</ext-link>)</p></caption><graphic xlink:href="thnov09p5049g006"></graphic></fig><fig id="F7" position="float"><label>Figure 7</label><caption><p><bold> MRP4 is involved in endometrial tumorigenesis <italic>in vitro</italic> and<italic> in vivo</italic>. A)</bold> Western blots for MRP4 in ISK cells after stable expression of 5 designs of shRNAs against MRP4 (shMRP4_1, 2, 3, 4 and 5) or non-silencing controls (shNC). GAPDH was used as the loading control. <bold>B-C)</bold> MTT assay (B) and colony formation (C) in ISK cells with MRP4 knockdown by shMRP4_2 or shMRP4_4, or shNC controls. n = 3. ***<italic> P</italic> < 0.001 by two-way ANOVA in B and one-way AVOVA in C. <bold>D-F)</bold> Photographs of dissected tumors (D), measurement of tumor volume (E) and weight (F) after ISK cells treated with shNC or shMRP4_4 were subcutaneously inoculated into the flanks of nude mice (3 x 10<sup>6</sup> cells per mouse) and grown for 26 days. n = 8. **<italic> P</italic> < 0.01, by two-way ANOVA in E, *<italic> P</italic> < 0.05 by Student's <italic>t</italic> test in F.</p></caption><graphic xlink:href="thnov09p5049g007"></graphic></fig><fig id="F8" position="float"><label>Figure 8</label><caption><p><bold>Schematic drawing showing the role of MRP4 in regulation of Wnt/β-catenin signaling in the endometrium.</bold> In endometrial epithelial cells, MRP4, through protein-protein interaction, stabilizes β-catenin (β-Cat) from degradation, which accumulates sufficient amount of β-catenin to translocate into the nucleus leading to the transcription of target genes of Wnt/β-catenin signaling pathway. Such a role of MRP4 in the endometrium is involved in both receptivity transition for embryo implantation and pathogenic transformation to develop endometriosis or endometrial cancer.</p></caption><graphic xlink:href="thnov09p5049g008"></graphic></fig><table-wrap id="T1" position="float"><label>Table 1</label><caption><p>Clinical data of subjects diagnosed of ovarian endometriosis</p></caption><table frame="hsides" rules="groups"><thead valign="top"><tr><th rowspan="1" colspan="1">Subject#</th><th rowspan="1" colspan="1">Age</th><th rowspan="1" colspan="1">Endometriosis Stage</th><th rowspan="1" colspan="1">Affected ovary (Unilateral or bilateral)</th><th rowspan="1" colspan="1">Number of gravidity (G) and parity (P)</th><th rowspan="1" colspan="1">Chronic pelvic pain (No/mild/medium/severe)</th></tr></thead><tbody valign="top"><tr><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">25</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">Severe</td></tr><tr><td rowspan="1" colspan="1">2</td><td rowspan="1" colspan="1">27</td><td rowspan="1" colspan="1">Undetermined</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">Medium</td></tr><tr><td rowspan="1" colspan="1">3</td><td rowspan="1" colspan="1">25</td><td rowspan="1" colspan="1">II</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">Medium</td></tr><tr><td rowspan="1" colspan="1">4</td><td rowspan="1" colspan="1">25</td><td rowspan="1" colspan="1">IV</td><td rowspan="1" colspan="1">Unilateral/Right</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">Severe</td></tr><tr><td rowspan="1" colspan="1">5</td><td rowspan="1" colspan="1">42</td><td rowspan="1" colspan="1">II</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G3P1</td><td rowspan="1" colspan="1">Mild</td></tr><tr><td rowspan="1" colspan="1">6</td><td rowspan="1" colspan="1">34</td><td rowspan="1" colspan="1">II</td><td rowspan="1" colspan="1">Unilateral/Right</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">Mild</td></tr><tr><td rowspan="1" colspan="1">7</td><td rowspan="1" colspan="1">32</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Right</td><td rowspan="1" colspan="1">G1P0</td><td rowspan="1" colspan="1">Medium</td></tr><tr><td rowspan="1" colspan="1">8</td><td rowspan="1" colspan="1">39</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Right</td><td rowspan="1" colspan="1">G1P0</td><td rowspan="1" colspan="1">Mild</td></tr><tr><td rowspan="1" colspan="1">9</td><td rowspan="1" colspan="1">31</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Bilateral</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">10</td><td rowspan="1" colspan="1">25</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">11</td><td rowspan="1" colspan="1">27</td><td rowspan="1" colspan="1">II</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G1P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">12</td><td rowspan="1" colspan="1">27</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G1P0</td><td rowspan="1" colspan="1">Medium</td></tr><tr><td rowspan="1" colspan="1">13</td><td rowspan="1" colspan="1">29</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Right</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">Medium</td></tr><tr><td rowspan="1" colspan="1">14</td><td rowspan="1" colspan="1">30</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Bilateral</td><td rowspan="1" colspan="1">G0P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">15</td><td rowspan="1" colspan="1">41</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G3P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">16</td><td rowspan="1" colspan="1">34</td><td rowspan="1" colspan="1">II</td><td rowspan="1" colspan="1">Bilateral</td><td rowspan="1" colspan="1">G2P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">17</td><td rowspan="1" colspan="1">29</td><td rowspan="1" colspan="1">IV</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G1P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">18</td><td rowspan="1" colspan="1">35</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Left</td><td rowspan="1" colspan="1">G1P0</td><td rowspan="1" colspan="1">No</td></tr><tr><td rowspan="1" colspan="1">19</td><td rowspan="1" colspan="1">42</td><td rowspan="1" colspan="1">III</td><td rowspan="1" colspan="1">Unilateral/Right</td><td rowspan="1" colspan="1">G2P1</td><td rowspan="1" colspan="1">No</td></tr></tbody></table></table-wrap></floats-group></pmc><affiliations><list><country><li>Hong Kong</li><li>République populaire de Chine</li></country><region><li>Guangdong</li></region><settlement><li>Jiangmen</li><li>Shenzhen</li></settlement></list><tree><noCountry><name sortKey="Chan, Hsiao Chang" sort="Chan, Hsiao Chang" uniqKey="Chan H" first="Hsiao Chang" last="Chan">Hsiao Chang Chan</name><name sortKey="Huang, Wen Qing" sort="Huang, Wen Qing" uniqKey="Huang W" first="Wen Qing" last="Huang">Wen Qing Huang</name><name sortKey="Jiang, Xiaohua" sort="Jiang, Xiaohua" uniqKey="Jiang X" first="Xiaohua" last="Jiang">Xiaohua Jiang</name><name sortKey="Ruan, Ye Chun" sort="Ruan, Ye Chun" uniqKey="Ruan Y" first="Ye Chun" last="Ruan">Ye Chun Ruan</name><name sortKey="Sun, Xiao" sort="Sun, Xiao" uniqKey="Sun X" first="Xiao" last="Sun">Xiao Sun</name><name sortKey="Wang, Yan" sort="Wang, Yan" uniqKey="Wang Y" first="Yan" last="Wang">Yan Wang</name><name sortKey="Yu, Mei Kuen" sort="Yu, Mei Kuen" uniqKey="Yu M" first="Mei Kuen" last="Yu">Mei Kuen Yu</name></noCountry><country name="République populaire de Chine"><region name="Guangdong"><name sortKey="Chen, Jun Jiang" sort="Chen, Jun Jiang" uniqKey="Chen J" first="Jun-Jiang" last="Chen">Jun-Jiang Chen</name></region><name sortKey="Chen, Hao" sort="Chen, Hao" uniqKey="Chen H" first="Hao" last="Chen">Hao Chen</name><name sortKey="Chen, Jun Jiang" sort="Chen, Jun Jiang" uniqKey="Chen J" first="Jun-Jiang" last="Chen">Jun-Jiang Chen</name><name sortKey="Duan, Yong Gang" sort="Duan, Yong Gang" uniqKey="Duan Y" first="Yong-Gang" last="Duan">Yong-Gang Duan</name><name sortKey="Meng, Xiaojing" sort="Meng, Xiaojing" uniqKey="Meng X" first="Xiaojing" last="Meng">Xiaojing Meng</name><name sortKey="Zou, Fei" sort="Zou, Fei" uniqKey="Zou F" first="Fei" last="Zou">Fei Zou</name></country><country name="Hong Kong"><noRegion><name sortKey="Xiao, Zhi Jie" sort="Xiao, Zhi Jie" uniqKey="Xiao Z" first="Zhi-Jie" last="Xiao">Zhi-Jie Xiao</name></noRegion><name sortKey="Wong, Maria Pik" sort="Wong, Maria Pik" uniqKey="Wong M" first="Maria Pik" last="Wong">Maria Pik Wong</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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