title: Krüppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis.
abstract: BACKGROUND
  Endometriosis is characterized by progesterone resistance and associated with infertility. Krüppel-like factor 9 (KLF9) is a progesterone receptor (PGR)-interacting protein, and mice null for Klf9 are subfertile. Whether loss of KLF9 expression contributes to progesterone resistance of eutopic endometrium of women with endometriosis is unknown.
  
  
  OBJECTIVE
  The aims were to investigate 1) KLF9 expression in eutopic endometrium of women with and without endometriosis, 2) effects of attenuated KLF9 expression on WNT-signaling component expression and on WNT inhibitor Dickkopf-1 promoter activity in human endometrial stromal cells (HESC), and 3) PGR and KLF9 coregulation of the stromal transcriptome network.
  
  
  METHODS
  Transcript levels of KLF9, PGR, and WNT signaling components were measured in eutopic endometrium of women with and without endometriosis. Transcript and protein levels of WNT signaling components in HESC transfected with KLF9 and/or PGR small interfering RNA were analyzed by quantitative RT-PCR and Western blot. KLF9 and PGR coregulation of Dickkopf-1 promoter activity was evaluated using human Dickkopf-1-luciferase promoter/reporter constructs and by chromatin immunoprecipitation. KLF9 and PGR signaling networks were analyzed by gene expression array profiling.
  
  
  RESULTS
  Eutopic endometrium from women with endometriosis had reduced expression of KLF9 mRNA together with those of PGR-B, WNT4, WNT2, and DKK1. KLF9 and PGR were recruited to the DKK1 promoter and modified each other's transactivity. In HESC, KLF9 and PGR coregulated components of the WNT, cytokine, and IGF gene networks that are implicated in endometriosis and infertility.
  
  
  CONCLUSIONS
  Loss of KLF9 coregulation of endometrial stromal PGR-responsive gene networks may underlie progesterone resistance in endometriosis.
authors.affiliation: Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, and the Arkansas Children's Nutrition Center, 15 Children's Way, Little Rock, Arkansas 72202, USA.
authors.forename: John Mark P
authors.initials: JM
authors.lastname: Pabona
authors.forename: Frank A
authors.initials: FA
authors.lastname: Simmen
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Nikiforov
authors.forename: DaZhong
authors.initials: D
authors.lastname: Zhuang
authors.forename: Kartik
authors.initials: K
authors.lastname: Shankar
authors.forename: Michael C
authors.initials: MC
authors.lastname: Velarde
authors.forename: Zara
authors.initials: Z
authors.lastname: Zelenko
authors.forename: Linda C
authors.initials: LC
authors.lastname: Giudice
authors.forename: Rosalia C M
authors.initials: RC
authors.lastname: Simmen
mesh_terms: D000328:Adult; D004715:Endometriosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D011980:Receptors, Progesterone