Expression and clinical significance of Glucose Regulated Proteins GRP78 (BiP) and GRP94 (GP96) in human adenocarcinomas of the esophagus

Background: Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis. Methods: Formalin-fixed, paraffin-embedded tissues of primary resected esophageal ( Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival. Results: GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pTIm and pTIsm) as compared to more advanced stages (pT2 and pT3) and normal tissue ( p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors ( p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit ( p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome. GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pTIm and pTIsm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage ( p = 0.001) and less lymph node involvement ( p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pTIm or pTIsm) or advanced ( pT3) tumor stages and no pT2 stage ( p = 0.031). Conclusion: We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response.