Abstract
BackgroundEsophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm.The glucocorticoid (GC)-glucocorticoid receptor (GR) pathway plays pivotal roles in cellular response to various stresses of tumor cells, including chemotherapy. However, the status of the GC-GR pathway in ESCC, including its correlation with chemotherapeutic responses, is largely unknown.MethodsGR, serum-and glucocorticoid-regulated kinase 1 (Sgk1), and N-myc down regulation gene 1 (NDRG1) were immunolocalized in 98 patients with ESCC who had undergone esophagectomy following neoadjuvant chemotherapy (NAC) with 2 courses of 5-fluorouracil + cisplatin. We also examined biopsy specimens before NAC in 42 cases and compared the results between those before and after NAC.ResultsOverall survival (OS) of the patients treated with surgery following NAC was significantly shorter in the group with high GR than that with low GR status (P = 0.0473). Both OS and disease-free survival (DFS) were significantly shorter in both Sgk1- and NDRG1-high groups than in the low groups (OS: Sgk1, P = 0.0055; NDRG1, P = 0.0021; DFS: Sgk1, P = 0.0240; NDRG1, P = 0.0086). Biopsy specimens before NAC showed significantly shorter DFS in the high Sgk1 group (P = 0.0095), while both OS and DFS were shorter in the high NDRG1 group (OS, P = 0.0233; DFS, P = 0.0006) than in the respective low groups. In the high NDRG1 group of biopsy specimens before NAC, the tumor reduction rate by NAC was significantly attenuated (P = 0.021).ConclusionsHigh GR, Sgk1, and NDRG1 statuses in ESCC after NAC was significantly associated with an overall worse prognosis, with no significant changes in their expression levels before and after NAC. Therefore, increased activity of the GC-GR pathway with enhanced induction of Sgk1 and NDRG1 in carcinoma cells play pivotal roles in tumor progression and development of chemo-resistance in patients with ESCC undergoing NAC.
Highlights
Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm
In surgical specimens following neoadjuvant chemotherapy (NAC), a high status of glucocorticoid receptor (GR), serum-and glucocorticoid-regulated kinase 1 (Sgk1), and N-myc down regulation gene 1 (NDRG1) was detected in 53.1% (52/98), 54.1% (53/98), and 38.8% (38/98) of the patients, respectively (Table 1)
Post-NAC status of GR, Sgk1, and NDRG1 in carcinoma cells and their correlation with patient survival Five-year Overall survival (OS) rate of the patients harboring high GR status was significantly shorter than those harboring low GR group (P = 0.0473) (Fig. 2a)
Summary
Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. The glucocorticoid (GC)-glucocorticoid receptor (GR) pathway plays pivotal roles in cellular response to various stresses of tumor cells, including chemotherapy. The standard treatment consists of surgical resection of locally advanced esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemotherapy (NAC) [2]. The glucocorticoid (GC)-glucocorticoid receptor (GR) signal pathway is well known to play pivotal roles in cellular response to various stresses [5]. This pathway was reported to be involved in the stress response of tumor cells and simultaneously reduce the effects of chemotherapy by enhancing cellular response to stress in various carcinoma cells [6].
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