Overexpression of cellular iron import proteins is associated with malignant progression of Esophageal adenocarcinoma
Overexpression of cellular iron import proteins is associated with malignant progression of Esophageal adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-07-1054
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发表时间：
2008-01-15
影响因子：
11.5
通讯作者：
Tselepis, Chris
中科院分区：
文献类型：
--
作者：
Boult, Jessica;Roberts, Keith;Tselepis, Chris
目的：越来越多的证据表明，铁在食管腺癌中很重要，食管腺癌的发病率上升速度比西方世界任何其他癌症都快。然而，铁如何在分子水平介导致癌作用仍不清楚。在本研究中，我们研究了癌前病变巴雷特化生和食管腺癌中参与细胞铁输入、输出和储存的铁转运蛋白的表达。实验设计：使用Perls染色来检查组织中的铁沉积。通过实时PCR检测与食管腺癌相匹配的Barrett化生样本和没有腺癌证据的Barrett化生样本中的mRNA表达。使用半定量免疫组织化学来检查细胞定位和蛋白质水平。分别使用溴脱氧尿苷测定和实时 PCR 测定食管细胞系 OE33 和 SEG-1 中铁负荷对细胞增殖和铁转运蛋白表达的影响。结果：在 Barrett 化生进展为腺癌的过程中，二价金属转运蛋白 1 (DMT1)、转铁蛋白受体 1、十二指肠细胞色素 b、铁转运蛋白和 H-铁蛋白过度表达，并且这些变化与这些变化相关随着铁沉积的增加。 DMT1 的过度表达进一步与转移性腺癌相关。铁负载的OE33和SEG-1细胞引起细胞增殖增加，这与H-铁蛋白增加和转铁蛋白受体1和DMT1表达减少有关。结论：腺癌的进展与铁输入蛋白表达增加有关。这些事件最终导致细胞内铁增加和细胞增殖。这可能代表了食管癌发生的一种新机制。
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.