Abstract
Background
Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. Glucocorticoid(GC)-Glucocorticoid receptor (GR) pathway plays pivotal roles in cellular response to various stresses of tumor cells including chemotherapy. However, the status of GC-GR pathway in ESCC, including its correlation with chemotherapeutic responses has remained largely unknown.
Method
GR, serum-and glucocorticoid-regulated kinase 1(Sgk1), and N-myc down regulation gene 1(NDRG1) were immunolocalized in 98 ESCC patients who had undergone esophagectomy following neoadjuvant chemotherapy(NAC) with 2 courses of 5-Fluorouracil(5-FU) + Cisplatin (CDDP). We also examined biopsy specimens before NAC in 42 cases and compared the results between those before and after NAC.
Results
Overall survival (OS) of the patients treated with surgery following NAC was significantly shorter in the group with high GR than that with low GR ( P = 0.0473). Both OS and disease-free survival (DFS) were significantly shorter in both Sgk1- and NDRG1-high groups than low groups (OS: Sgk1, P = 0.0055; NDRG1, P = 0.0021; DFS: Sgk1, P = 0.0240; NDRG1, P = 0.0086). When evaluating the findings in biopsy specimens before NAC, DFS was significantly shorter in the high Sgk1 group ( P = 0.0095), and both OS and DFS was shorter in high NDRG1 group (OS, P = 0.0233; DFS, P = 0.0006) than respective low groups. Among high NDRG1 group of biopsy specimens before NAC, the tumor reduction rate by NAC was significantly attenuated ( P = 0.021).
Conclusions
High status of GR, Sgk1, and NDRG1 in ESCC after NAC was significantly associated with over all worse prognosis and there were no significant changes in the status of those above before and after NAC. Therefore , increased activity of GC-GR pathway with enhanced induction of Sgk1 and NDRG1 in carcinoma cells plays pivotal roles in tumor progression and development of chemoresistance in ESCC patients undergoing NAC.
GR, Sgk1, and NDRG1 in esophageal squamous cell carcinoma: their correlation with therapeutic outcome of neoadjuvant chemotherapy