title: Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction.
abstract: Abnormal trophoblast function is associated with fetal growth restriction (FGR). The JAK-STAT pathway is one of the principal signalling mechanisms by which cytokines and growth factors modulate cell proliferation, differentiation, cell migration and apoptosis. The expression of placental JAK-STAT genes in human idiopathic FGR is unknown. In this study, we propose the hypothesis that JAK-STAT pathway genes are differentially expressed in idiopathic FGR-affected pregnancies and contribute to abnormal feto-placental growth by modulating the expression of the amino acid transporter SNAT2, differentiation marker CGB/human chorionic gonadotrophin beta-subunit (β-hCG) and apoptosis markers caspases 3 and 8, and TP53. Expression profiling of FGR-affected placentae revealed that mRNA levels of STAT3, STAT2 and STAT5B decreased by 69, 52 and 50%, respectively, compared with gestational-age-matched controls. Further validation by real-time PCR and immunoblotting confirmed significantly lower STAT3 mRNA and STAT3 protein (total and phosphorylated) levels in FGR placentae. STAT3 protein was localised to the syncytiotrophoblast (ST) in both FGR and control placentae. ST differentiation was modelled by in vitro differentiation of primary villous trophoblast cells from first-trimester and term placentae, and by treating choriocarcinoma-derived BeWo cells with forskolin in cell culture. Differentiation in these models was associated with increased STAT3 mRNA and protein levels. In BeWo cells treated with siRNA targeting STAT3, the mRNA and protein levels of CGB/β-hCG, caspases 3 and 8, and TP53 were significantly increased, while that of SNAT2 was significantly decreased compared with the negative control siRNA. In conclusion, we report that decreased STAT3 expression in placentae may contribute to abnormal trophoblast function in idiopathic FGR-affected pregnancies.
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Borg
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: H E J
authors.initials: HE
authors.lastname: Yong
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Lappas
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesP
authors.forename: S A
authors.initials: SA
authors.lastname: Degrelle
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: R J
authors.initials: RJ
authors.lastname: Keogh
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Da Silva-Costa
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Fournier
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Abumaree
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Keelan
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Kalionis
authors.affiliation: Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia Department of Perinatal MedicinePregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, AustraliaDepartment of Obstetrics and GynaecologyUniversity of Melbourne, Melbourne, Victoria, AustraliaDepartment of Obstetrics and GynaecologyMercy Hospital for Women, Heidelberg, Victoria, AustraliaINSERM-U767Faculté des Sciences Pharmaceutiques et Biologiques, Paris F-75006, FranceUniversite Paris DescartesParis F-75006, FrancePremUp FoundationParis F-75006, FranceCollege of Science and Health ProfessionsKing Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaSchool of Women's and Infants' HealthKing Edward Memorial Hospital, University of Western Australia, Subiaco, Western Australia, Australia padma.murthi@monash.edu.
authors.forename: P
authors.initials: P
authors.lastname: Murthi
mesh_terms: D000328:Adult; D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007230:Infant, Low Birth Weight; D008297:Male; D010920:Placenta / Q000166:cytology* / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology*
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human