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

Abstract

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

RAGE Expression in Rhabdomyosarcoma Cells Results in Myogenic Differentiation and Reduced Proliferation, Migration, Invasiveness, and Tumor Growth

“…These observations are at variance with data obtained with glioma, melanoma, colon cancer, and human pancreatic carcinoma cells, 24 -27 in which a positive correlation was found among RAGE expression, neoplastic transformation, and metastasis, but are consistent with the differentiating activity of HMGB1/RAGE in neurons and L6 myoblasts. 11,34 However, our data are consistent with observations made with non-small lung carcinoma cells, 58 in which down-regulation of RAGE was found to be associated with neoplastic transformation and with previous work showing that RAGE-induced neuronal differentiation is associated with proliferation arrest. 26 The reduced proliferation of TE671/RAGE cells in vitro compared with TE671/wt and TE671/RAGE⌬cyto cells is accompanied by an increased induction of the proliferation inhibitor p21 WAF1 and remarkably decreased levels of cyclin D1 and extent of ERK1/2 and Rb phosphorylation.…”

Expression of the receptor for advanced glycation end-products and frequency of polymorphism in lung cancer

“…In colon cancer, joint expression of RAGE and HMGB1 was found to lead to enhanced migration in the cancer cell line, and the level of expression of RAGE and HMGB1 increased with the stage of cancer (12). By contrast, in lung cancer, a higher tumor stage was reported to be characterized by a downregulation in RAGE expression at the mRNA and protein levels (7). The present study confirmed that the expression of RAGE was downregulated in lung cancer tissue compared with noncancerous tissue from the same patient.…”

Critical role of RAGE in lung physiology and tumorigenesis: a potential target of therapeutic intervention?

“…Normal ATI cell differentiation and phenotype [22,50,51] Normal: embryonic stages [50,51] Tumorigenesis: cancer cell regression to embryonic phenotypes [37,[52][53][54][55][56][57][58] Normal ATI cell adhesion, spreading and stability [22] Decreased adhesiveness, increased migration, enhanced invasiveness [15,22,37,59-61] Normal alveolar cell apoptosis Evasion of apoptosis [15,16,29,59, 60] Normal alveolar function -gas exchange [22,62] Malignant behavior [59,60,61,63] Normal lung architecture [22,64] Malignant tissue and tumor stroma reorganization and modification [15,16,29,59-61] Normal cell-to-cell and cell-to-matrix communication Disruption of normal communication -cell isolation and autonomy explain the difference in binding affinity between different ligands, since each one of them possesses its own specific electrostatic signal. Touré et al showed that neutrophils exhibit enhanced adhesiveness and decreased migration on AGE-modified collagen in comparison to non-modified collagen [68].…”

“…Lung cancer, one of the most invasive malignancies, expresses low levels of RAGE [37], which correlate positively to increased tumor growth and invasiveness [59,60]. Furthermore, RAGE genes may have a role in the diagnosis of lung neoplasms, since they can be employed for the discrimination between normal and malignant lung tissues [96,97].…”

“…Furthermore, a study of lung specimens from tumor and paired non-tumor tissues of 34 NSCLC patients, who underwent pulmonary resection surgery, showed that the reduced mRNA level of RAGE in NSCLC correlated with higher tumor stages [59]. Since the differences were even more prominent at the protein level, further post-transcriptional regulation must take place.…”