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Overexpression of Cellular Iron Import Proteins Is Associated with Malignant Progression of Esophageal Adenocarcinoma

Authors' Affiliations: ¹ Cancer Research UK Institute for Cancer Studies, University of Birmingham; ² Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom; ³ Academic Unit of Pathology, University of Sheffield Medical School, Sheffield, United Kingdom; and ⁴ Iron Metabolism Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia

Requests for reprints: Chris Tselepis, Cancer Research UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Birmingham B15 2TH, United Kingdom. Phone: 44-121-414-2972; Fax: 44-121-627-2384; E-mail: c.tselepis{at}bham.ac.uk.

Purpose: 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.

Experimental Design: 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.