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

Abstract

Purpose:There is growing evidence that iron is important in esophageal adenocarcinoma, a cancer whose incidence is rising faster than any other in theWestern 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 DMT1was 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 1and DMT1expression. 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.

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

“…The Uppsala cohort was used (21). Of the 251 tumors in this cohort, 228 showed correlation of >0.1 with at least one subtype; the remaining 23 were classified as “no subtype” and censored.…”

“…Ferroportin has not been extensively studied in cancer (20, 21), and only limited examination of ferroportin has been made outside the tissues generally thought to be important in systemic iron homeostasis, such as the intestine, liver, bone marrow, and reticuloendothelial system (22). Because ferroportin has a central role in iron regulation, was among the genes decreased in breast cancer samples in an in silico analysis of the UniGene database (23), and is expressed in rat mammary epithelium (24), we examined ferroportin in human breast tumors.…”

Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

“…10,11 Hence, iron chelators are under study as potential antineoplastic drugs. 12 Oxidative stress is believed to play a role in ironinduced carcinogenesis, possibly by regulating CyclinD1, p27 and Cdk2, whereas iron depletion may halt the cell cycle progression by modulating the expression of p21 and Cyclin D1.…”

Polyethylene glycol–polylactic acid nanoparticles modified with cysteine–arginine–glutamic acid–lysine–alanine fibrin-homing peptide for glioblastoma therapy by enhanced retention effect

“…11 Unfortunately, the receptor-targeting drug-delivery system was not perfect, because the relative expression of those commonly used target receptors of BBB or GBM cells was not high enough and the GBM-targeting efficiency was still moderate, which led to limited treatment effect. 11,19,20 For instance, as a classic tumor-associated receptor, transferrinreceptor expression is upregulated in tumor cells only threeto fivefold higher than that in normal tissues. 19,20 Moreover, few studies have focused on NP retention in tumor tissue for the improvement of GBM treatment.…”

“…11,19,20 For instance, as a classic tumor-associated receptor, transferrinreceptor expression is upregulated in tumor cells only threeto fivefold higher than that in normal tissues. 19,20 Moreover, few studies have focused on NP retention in tumor tissue for the improvement of GBM treatment. Therefore, alternative therapeutic approaches targeting GBM with high efficiency are still urgently needed.…”