title: The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes.
abstract: Premature prelabor rupture of fetal membranes accounts for 30% of all premature births and is associated with detrimental long-term infant outcomes. Premature cervical remodeling, facilitated by matrix metalloproteinases, may trigger rupture at the zone of the fetal membranes overlying the cervix. The similarities and differences underlying cervical remodeling in premature prelabor rupture of fetal membranes and spontaneous preterm labor with intact membranes are unexplored.
  
  
  
  We aimed to perform the first transcriptomic assessment of the preterm human cervix to identify differences between premature prelabor rupture of fetal membranes and preterm labor with intact membranes and to compare the enzymatic activities of matrix metalloproteinases-2 and -9 between premature prelabor rupture of fetal membranes and preterm labor with intact membranes.
  
  
  
  Cervical biopsies were collected following preterm labor with intact membranes (n = 6) and premature prelabor rupture of fetal membranes (n = 5). Biopsies were also collected from reference groups at term labor (n = 12) or term not labor (n = 5). The Illumina HT-12 version 4.0 BeadChips microarray was utilized, and a novel network graph approach determined the specificity of changes between premature prelabor rupture of fetal membranes and preterm labor with intact membranes. Quantitative reverse transcription-polymerase chain reaction and Western blotting confirmed the microarray findings. Immunofluorescence was used for localization studies and gelatin zymography to assess matrix metalloproteinase activity.
  
  
  
  PML-RARA-regulated adapter molecule 1, FYVE-RhoGEF and PH domain-containing protein 3 and carcinoembryonic antigen-ralated cell adhesion molecule 3 were significantly higher, whereas N-myc downstream regulated gene 2 was lower in the premature prelabor rupture of fetal membranes cervix when compared with the cervix in preterm labor with intact membranes, term labor, and term not labor. PRAM1 and CEACAM3 were localized to immune cells at the cervical stroma and NDRG2 and FGD3 were localized to cervical myofibroblasts. The activity of matrix metalloproteinase-9 was higher (1.22 ± 4.403-fold, P < .05) in the cervix in premature prelabor rupture of fetal membranes compared with preterm labor with intact membranes.
  
  
  
  We identified 4 novel proteins with a potential role in the regulation of cervical remodeling leading to premature prelabor rupture of fetal membranes. Our findings contribute to the studies dissecting the mechanisms underlying premature prelabor rupture of fetal membranes and inspire further investigations toward the development of premature prelabor rupture of fetal membranes therapeutics.
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, Medical Research Council Centre for Reproductive Health, Edinburgh, United Kingdom. Electronic address: makievasofia@gmail.com.
authors.forename: Sofia
authors.initials: S
authors.lastname: Makieva
authors.affiliation: Deparment of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
authors.forename: Aurelija
authors.initials: A
authors.lastname: Dubicke
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, Medical Research Council Centre for Reproductive Health, Edinburgh, United Kingdom.
authors.forename: Sara F
authors.initials: SF
authors.lastname: Rinaldi
authors.affiliation: Deparment of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Fransson
authors.affiliation: Deparment of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
authors.forename: Gunvor
authors.initials: G
authors.lastname: Ekman-Ordeberg
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, Medical Research Council Centre for Reproductive Health, Edinburgh, United Kingdom.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Norman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D001706:Biopsy; D002272:Carcinoembryonic Antigen / Q000032:analysis; D002584:Cervix Uteri / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics / Q000503:physiopathology*; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis; D006801:Humans; D007743:Labor, Obstetric; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011247:Pregnancy; D040081:Protein Array Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C075729:CEACAM3 protein, human; D002272:Carcinoembryonic Antigen; C549833:FGD3 protein, human; D020662:Guanine Nucleotide Exchange Factors; C466228:NDRG2 protein, human; C430907:PRAM1 protein, human; D025521:Tumor Suppressor Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: cervix; metalloproteinases; microarray; premature rupture of fetal membranes; preterm labor