The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in visceral adipocytes predicts endometrial cancer progression and patient survival

Abstract

Objective Currently, accurately identifying endometrial cancer patients at high risk for recurrence remains poor. To ascertain if changes in the endoplasmic reticulum (ER) stress marker, glucose-regulated-protein-78 (GRP78) can serve as a prognosticator in endometrial cancer, we examined GRP78 expression in patient samples to determine its association with clinical outcome. Methods A retrospective cohort study was conducted in endometrial cancer patients. Archived specimens of visceral adipocytes and paired endometrial tumors were analyzed by immunohistochemistry for GRP78 and another ER stress marker, C/EBP homologous protein (CHOP). Expression of these markers was correlated with clinico-pathological information and outcomes. Results GRP78 expression in visceral adipocytes was detected in 95% of the 179 endometrial cancer patients with analyzable visceral adipocytes. Within individual samples, 24% of adipocytes (range, 0-90%, interquartile range 18%-38%) exhibited GRP78 expression. High visceral adipocyte GRP78 expression positively correlated with advanced-stage disease (p=0.007) and deep myometrial invasion (p=0.004). High visceral adipocyte GRP78 expression was significantly associated with decreased disease-free survival (DFS) in multivariate analyses (hazard ratio 2.88, 95% CI 1.37-6.04, p=0.005). CHOP expression paralleled the GRP78 expression in adipocytes (r=0.55, p<0.001) and in the tumor (p=0.018). Conclusions Our study demonstrates that the ER stress markers, GRP78 and CHOP, are elevated in endometrial cancer patients. Furthermore, GRP78 expression levels in visceral adipocytes from these patients were significantly correlated to disease stage and patient survival. Our results demonstrate, for the first time, that the GRP78 levels in endometrial cancer patients may be a prognosticator and aid with clinical risk stratification and focused surveillance.

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

“…GRP78, a molecular chaperone protein and a member of the heat shock protein-70 family, is critical for tumor progression and chemoresistance. GRP78 has also been shown to be negatively associated with cell survival [52]. Jiang et al revealed that ERS upregulates GRP78 protein levels in human pancreatic cancer cells [53].…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…In addition, activation of all the UPR branches was described in cellular and animal models of BRAF-, RAS-, MYC-, RET-, or HER2-driven tumorigenesis [reviewed in (29)]. Overexpression of the key regulator of ER stress response GRP78 was also frequently reported in tumor tissues and was associated with reduced patient survival (30)(31)(32). The concept of ER proteostasis addiction has been proposed as a mechanism supporting tumor growth and malignant cell transformation (33).…”

Expression and significance of glucose-regulated protein 78 in human osteosarcoma

“…In a retrospective cohort study, it was revealed that high GRP78 expression in visceral adipocytes from endometrial cancer patients was positively correlated with advanced-stage disease, deep myometrial invasion and decreased disease-free survival time (26). Park et al (17) also demonstrated that the overexpression of GRP78 in patients with ureter tumors was associated with a high tumor (T) stage and nuclear grade, a high bladder cancer recurrence rate and a low survival rate.…”