title: Decreased Endometrial Expression of Leukemia Inhibitory Factor Receptor Disrupts the STAT3 Signaling in Adenomyosis During the Implantation Window.
abstract: Adenomyosis was found to have negative impacts on embryo implantation. Leukemia inhibitory factor (LIF), proposed to be a molecular marker for endometrial receptivity, works through the LIF receptor (LIFR) on both the embryo and the endometrium. We aimed to evaluate the endometrial expression of LIF and LIFR and its subsequent signaling in patients with adenomyosis during the window of implantation (WOI).
  
  
  
  Endometrium was obtained during the WOI from patients with adenomyosis (age <45 years) who underwent hysterectomy and from age-matched controls who had no endometriosis or adenomyosis. The LIF and LIFR expressions were measured by polymerase chain reaction for messenger RNA expression, immunohistochemistry for protein intensity and localization, and immunofluorescent staining for colocalization. The ratio of signal transducer and activator of transcription 3 (STAT3) to extracellular signal-regulated kinase (ERK) phosphorylation was measured by Western blot of both the endometrium and the isolated human endometrial stromal cells (ESCs).
  
  
  
  Patients with adenomyosis showed significantly and parallelly reduced LIF and LIFR expressions in the eutopic endometrium during WOI as compared with the control women and subsequently with remarkably reduced activation of STAT3 and ERK signaling. The significantly increased STAT3 and ERK phosphorylation induced by the LIF treatment in the cultured ESCs supported the linkage between the LIF-LIFR reaction and the signaling cascade.
  
  
  
  Significant reduction in LIFR expression and the reduced activation of subsequent signaling strongly suggest a working model of how the implantation markers, LIF, may affect the endometrium of patients with adenomyosis. These molecular changes supported the declined implantation rates reported in patients with adenomyosis.
authors.affiliation: 1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Kwei-Shan, Taoyuan, Taiwan.|2 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chih-Feng
authors.initials: CF
authors.lastname: Yen
authors.affiliation: 2 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taipei, Taiwan.|3 The PhD Program of Cancer Biology and Drug Discovery, Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shuen-Kuei
authors.initials: SK
authors.lastname: Liao
authors.affiliation: 4 Department of Obstetrics and Gynecology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.|5 Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Huang
authors.affiliation: 6 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Selcuk
authors.initials: S
authors.lastname: Tabak
authors.affiliation: 7 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Arcuri
authors.affiliation: 8 Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Keelung, Taiwan.
authors.forename: Chyi-Long
authors.initials: CL
authors.lastname: Lee
authors.affiliation: 6 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Aydin
authors.initials: A
authors.lastname: Arici
authors.affiliation: 7 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Petraglia
authors.affiliation: 1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Kwei-Shan, Taoyuan, Taiwan.|2 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Hsin-Shih
authors.initials: HS
authors.lastname: Wang
authors.affiliation: 5 Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Umit A
authors.initials: UA
authors.lastname: Kayisli
mesh_terms: D062788:Adenomyosis / Q000378:metabolism*; D015226:Dinucleoside Phosphates; D010064:Embryo Implantation / Q000502:physiology*; D004717:Endometrium / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D053606:Receptors, OSM-LIF / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: C472178:3'-amino-3'-deoxyuridylyl-3',5'-uridine; D015226:Dinucleoside Phosphates; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: adenomyosis; endometrium; leukemia inhibitory factor (LIF); signal transducer and activator of transcription (STAT) 3; window of implantation (WOI)