Carcinogenesis Advance Access originally published online on November 11, 2004
Carcinogenesis 2005 26(2):293-301; doi:10.1093/carcin/bgh333
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Carcinogenesis vol.26 no.2 © Oxford University Press 2005; all rights reserved.
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Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma
Clinic of Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Strasse 40, D-06120 Halle/Saale, Germany and 1 Institute of Immunology, Technical University Dresden, Dresden, Germany
* To whom correspondence should be addressed. Tel: +49 345 557 3314; Fax: +49 345 557 7070; Email: babett.bartling{at}medizin.uni-halle.de
The receptor for advanced glycation end-products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily. Several ligands binding to RAGE have been identified, including amphoterin. Experimental studies have given rise to the discussion that RAGE and its interaction with amphoterin contribute to tumour growth and metastasis. However, none of the studies considered a differential transcription profile in cancer that might change the interpretation of the study results when comparing RAGE in tumours with histologically normal tissues. Here we show that RAGE is strongly reduced at the mRNA and even more so at the protein level in non-small cell lung carcinomas compared with normal lung tissues. Down-regulation of RAGE correlates with higher tumour (TNM) stages but does not depend on the histological subtypes, squamous cell lung carcinoma and adenocarcinoma. Subsequent overexpression of full-length human RAGE in lung cancer cells (NCI-H358) showed diminished tumour growth under some conditions. While proliferation of RAGE-expressing cells was less than that of cells expressing the cytoplasmic domain deletion mutant 
cytoRAGE or mock-transfected NCI-H358 in monolayer cultures, RAGE cells also formed smaller tumours in spheroid cultures and in vivo in athymic mice compared with cytoRAGE cells. Moreover, we observed a more epithelial growth of RAGE-expressing, but also of cytoRAGE-expressing, cells on collagen layers, whereas mock NCI-H358 cells kept their tumour morphology. This observation was supported by immunofluorescence analyses demonstrating that RAGE preferentially localizes at intercellular contact sites, independent of expression of the cytoplasmic domain. Thus, down-regulation of RAGE may be considered as a critical step in tissue reorganization and the formation of lung tumours.
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