title: Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma.
abstract: OBJECTIVE
  There is growing evidence that iron is important in esophageal adenocarcinoma, a cancer whose incidence is rising faster than any other in the Western world. However, how iron mediates carcinogenesis at the molecular level remains unclear. In this study, we investigated the expression of iron transport proteins involved in cellular iron import, export, and storage in the premalignant lesion Barrett's metaplasia and esophageal adenocarcinoma.
  
  
  METHODS
  Perls' staining was used to examine iron deposition in tissue. mRNA expression in samples of Barrett's metaplasia matched with esophageal adenocarcinoma and samples of Barrett's metaplasia without evidence of adenocarcinoma were examined by real-time PCR. Semiquantitative immunohistochemistry was used to examine cellular localization and protein levels. The effect of iron loading on cellular proliferation and iron transporter expression was determined in esophageal cell lines OE33 and SEG-1 using a bromodeoxyuridine assay and real-time PCR, respectively.
  
  
  RESULTS
  In the progression of Barrett's metaplasia to adenocarcinoma, there was overexpression of divalent metal transporter 1 (DMT1), transferrin receptor 1, duodenal cytochrome b, ferroportin, and H-ferritin, and these changes were associated with increased iron deposition. Overexpression of DMT1 was further associated with metastatic adenocarcinoma. Iron loading OE33 and SEG-1 cells caused increased cellular proliferation, which was associated with increased H-ferritin and decreased transferrin receptor 1 and DMT1 expression.
  
  
  CONCLUSIONS
  Progression to adenocarcinoma is associated with increased expression of iron import proteins. These events culminate in increased intracellular iron and cellular proliferation. This may represent a novel mechanism of esophageal carcinogenesis.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, University of Birmingham, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Boult
authors.forename: Keith
authors.initials: K
authors.lastname: Roberts
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brookes
authors.forename: Sharon
authors.initials: S
authors.lastname: Hughes
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bury
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.forename: Robert
authors.initials: R
authors.lastname: Spychal
authors.forename: Tariq
authors.initials: T
authors.lastname: Iqbal
authors.forename: Chris
authors.initials: C
authors.lastname: Tselepis
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000503:physiopathology*; D015703:Antigens, CD / Q000378:metabolism; D001052:Apoferritins / Q000378:metabolism; D001471:Barrett Esophagus / Q000378:metabolism / Q000503:physiopathology*; D027682:Cation Transport Proteins / Q000378:metabolism*; D003573:Cytochrome b Group / Q000378:metabolism; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D015703:Antigens, CD; D001052:Apoferritins; D027682:Cation Transport Proteins; D003573:Cytochrome b Group; D007501:Iron; D010088:Oxidoreductases; D011990:Receptors, Transferrin; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C068126:CD71 antigen; C422926:CYBRD1 protein, human