Interferon‐inducible guanylate binding protein (GBP)‐2: A novel p53‐regulated tumor marker in esophageal squamous cell carcinomas

TP53 mutations are common in esophageal squamous cell carcinomas (SCC). To identify biological markers of possible relevance in esophageal SCC, we (i) searched for genes expressed in a p53-dependent manner in TE-1, an esophageal SCC cell line expressing the temperature-sensitive TP53 mutant V272M, and (ii) investigated the expression of one of those genes, the interferon-inducible Guanylate Binding Protein 2 (GBP-2), in esophageal SCC tissues. Clontech Human Cancer 1.2 arrays containing 1,176 human cancer gene-related sequences were used to identify differentially expressed genes in TE-1 cells at permissive (32 degrees C) and nonpermissive (37 degrees C) temperatures. The expression of GBP-2 and IRF-1, its main transcriptional regulator, was analyzed by immunohistochemistry in a retrospective series of 41 esophageal SCC cases with a clear transition zone from noncancer, apparently normal epithelium to invasive cancer. The expression of the GBP-2 gene is consistently increased in TE-1 at 32 degrees C in a p53-dependent manner, as confirmed by inhibition of p53 expression by RNA interference. Increase in GBP-2 is accompanied by an increase in protein levels of IRF-1, the main transcriptional regulator of GBP-2, and in the formation of complexes between p53 and IRF-1. GBP-2 expression is significantly higher in esophageal SCC than in adjacent normal epithelium (p<0.01), in which GBP-2 staining is limited to the basal layer. Our results suggest that p53 up-regulates GBP-2 by cooperating with IRF-1. The association of GBP-2 expression with proliferative squamous cells suggests that GBP-2 may represent a marker of interest in esophageal SCC.