Journal Article

Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma

Babett Bartling, Hans-Stefan Hofmann, Bernd Weigle, Rolf-Edgar Silber and Andreas Simm

in Carcinogenesis

Volume 26, issue 2, pages 293-301
Published in print February 2005 | ISSN: 0143-3334
Published online February 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh333
Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma

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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 ΔcytoRAGE 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 ΔcytoRAGE cells. Moreover, we observed a more epithelial growth of RAGE-expressing, but also of ΔcytoRAGE-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.

Keywords: AdCa, adenocarcinoma; ATI, type I lung alveolar; CPD, cumulative population doubling; DCL-1, deleted in liver cancer; DMEM, Dulbecco's modified Eagle's medium; GFP, green fluorescent protein; NF-κB, nuclear factor κB; NSCLC, non-small cell lung carcinomas; PBS, phosphate-buffered saline; PI, propidium iodide; RAGE, receptor for advanced glycation end-products; SCCa, squamous cell lung carcinoma

Journal Article.  7133 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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