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

Abstract

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°C) and nonpermissive (37°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°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.

Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus

“…In agreement with the observation in the ESSC tissue samples described above, EZH2 expression in TE-1 cells was significantly reduced when cultured at 32˚C. Since TE-1 cells express a mutant P53 protein that exhibits transcriptional activity at 32˚C, but not at 37˚C (38), our findings suggest that impaired transcriptional activity of P53 protein may cause upregulation of EZH2 in TE1 cells. Taken together, our observations suggest that P53 alteration and impaired transcriptional activity may have a role in the dysregulation of EZH2 expression in ESCC cells.…”

“…DNA consensus sequences and that exhibits transcriptional activity at 32˚C but not at 37˚C (38). Consistent with these characteristics we observed significant upregulation of the P53 target genes MDM2 and P21 when TE-1 cells were cultured at 32˚C (data not shown) and expression of EZH2 mRNA in TE-1 cells was significantly lower when cultured at 32˚C than at 37˚C.…”

“…Human esophageal squamous cell carcinoma cell lines TE-1 and TE-10 were purchased from the RIKEN BRC (Tsukuba, Japan). TE-1 is known to express a temperaturesensitive mutant P53 protein (codon 272, valine to methionine), which is capable of binding to specific DNA consensus sequences at 32˚C but not at 37˚C (38). TE-10 cells express a mutant P53 protein (codon 242, cysteine to tyrosine) that displays no specific DNA-binding activity (39).…”

Transcriptional regulation of thymine DNA glycosylase (TDG) by the tumor suppressor protein p53

“…However, at 37°C (restrictive temperature), the protein folds into a "mutant" form unable to specifically bind DNA and to regulate gene expression in a p53-dependent manner. 24 Although the conformational and functional shift is only partial (at 32°C a significant fraction of…”

465 Rna Sequencing Reveals Up-Regulation of Runx1-Runx1t1 Gene Signatures in Clear Cell Renal Cell Carcinoma

“…GBP2 belongs to the family of GTP-binding proteins with limited known function. Recently, it has been reported that GBP2 may be mediated by p53 and become a disease marker in esophageal cancer [31]. VCAN, however, has been previously reported to be upregulated in RCC.…”