title: Inflammatory mediators of esophagitis alter p27 Kip1 expression in esophageal epithelial cells.
abstract: BACKGROUND
  Barrett esophagus (BE) is a premalignant condition that develops due to prolonged gastroesophageal reflux disease (GERD). In some but not all cases, BE progresses to Barrett-associated adenocarcinoma. p27 is a tumor-suppressor protein that regulates the cell's division cycle and appears to be frequently inactivated in Barrett-associated adenocarcinoma due to increased degradation or cytoplasmic mislocalization. Reduced or mislocalized p27 would remove it from its nuclear targets and result in increased proliferation. Although bile acid and hydrochloric acid (HCl) are linked to the pathogenesis of BE, not every patient with BE has a history of GERD. Eosinophilic esophagitis mimics GERD, but eosinophil granule proteins, known to mediate inflammation, have not been linked to BE. It was unknown whether mediators of esophagitis affect p27 expression and/or localization in normal esophageal cells. We assessed the effects of bile acid, HCl, and eosinophil granule proteins on p27 protein expression, localization, and its ability to regulate cell proliferation.
  
  
  METHODS
  Human esophageal epithelial (HET-1A) cells were incubated with chenodeoxycholic acid (CDC), HCl, and eosinophil granule proteins (major basic protein, MBP; and eosinophil peroxidase, EPO). Cell viability analysis, immunoblot, immunofluorescence microscopy, and flow cytometric analysis were performed.
  
  
  RESULTS
  Exposure of HET-1A cells to CDC, HCl, MBP, and EPO did not affect total p27 levels. CDC, HCl, MBP, and EPO caused mislocalization of p27 from the nucleus to the cytoplasm. Flow cytometry showed that CDC exposure also increased HET-1A cell proliferation.
  
  
  CONCLUSIONS
  Mislocalization of p27 caused by mediators of GERD or eosinophilic esophagitis may serve as an early marker of increased cell proliferation, which may contribute to the risk for esophageal dysplasia.
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, SUNY Downstate Medical Center, Brooklyn, NY, USA. kimnguyen@mcg.edu
authors.forename: Kim-Doan Katrina
authors.initials: KD
authors.lastname: Nguyen
authors.forename: Stacy W
authors.initials: SW
authors.lastname: Blain
authors.forename: Frank
authors.initials: F
authors.lastname: Gress
authors.forename: William R
authors.initials: WR
authors.lastname: Treem
mesh_terms: D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002635:Chenodeoxycholic Acid; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D047091:Eosinophil Granule Proteins; D057765:Eosinophilic Esophagitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004804:Eosinophils / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D005764:Gastroesophageal Reflux / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006851:Hydrochloric Acid; D018836:Inflammation Mediators / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D047091:Eosinophil Granule Proteins; D018836:Inflammation Mediators; D002635:Chenodeoxycholic Acid; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006851:Hydrochloric Acid