The receptor for advanced glycosylated end products (RAGE), a member of the immunoglobulin superfamily, was one of the cDNA subtraction clones that was found to be differentially expressed in human lung and the corresponding tumor tissue. In nine additional matched normal/tumor pairs, a strongly reduced or missing expression, not only on a transcriptional level but also on a protein level, was demonstrated in the non-small cell lung carcinoma tissue. Because amphoterin, a physiological ligand of RAGE that is highly expressed in the lung, mediates cell differentiation via RAGE, a down-regulation of the receptor may be considered as a critical step in lung tumor formation. Furthermore, we determined the complete reading frame of RAGE.