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Although selective COX-2 inhibitors have cancer-preventive effects and induce apoptosis, the mechanisms underlying these effects are not fully understood. This study investigated the effects of nimesulide, a selective COX-2 inhibitor, on apoptosis and on the JAK/STAT signaling pathway in Eca-109 human esophageal squamous carcinoma cells. The effects and mechanisms of nimesulide on Eca-109 cell growth were studied in culture and in nude mice with Eca-109 xenografts. Cells were cultured with or without nimesulide and/or the JAK2 inhibitor AG490. Cell proliferation was evaluated using the MTT assay, and apoptosis was investigated. COX-2 mRNA expression was measured using reverse transcription polymerase chain reaction, and protein expression was detected by Western blot analysis, immunohistochemistry, and flow cytometry. Nimesulide significantly inhibited Eca-109 cell viability in vitro in a dose- and time-dependent manner (P<0.05). Nimesulide also induced apoptosis, which was accompanied by a significant decrease in the expression of COX-2 and survivin and an increase in caspase-3 expression. Nimesulide downregulated the phosphorylation levels of JAK2 and STAT3, and JAK2 inhibition by AG490 significantly augmented both nimesulide-induced apoptosis and the downregulation of COX-2 and survivin (P<0.05). In vivo, nimesulide inhibited the growth of Eca-109 tumors and the expression of p-JAK2 and p-STAT3. Thus, nimesulide downregulates COX-2 and survivin expression and upregulates caspase-3 expression in Eca-109 cells, by inactivating the JAK2/STAT3 pathway. These effects may mediate nimesulide-induced apoptosis and growth inhibition in Eca-109 cells in vitro and in vivo., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Background & Objective: Cyclooxygenase-2 (COX-2) and signal transducers and activators of transcription (STAT) are closely correlated to the genesis of tumors. This study was to investigate the expression and clinical significance of COX-2, p-Stat3 and p-Stat5 (the activated forms of Stat3 and Stat5) in various lesions of esophageal tissues, and to analyze their correlations to clinicopathologic features of esophageal squamous cell carcinoma (ESCC)., Methods: The expression of COX-2, p-Stat3, and p-Stat5 in 59 specimens of ESCC, 24 specimens of squamous dysplasia, and 18 specimens of normal squamous epithelium was examined by SP immunohistochemistry. Their correlations to clinicopathologic features of ESCC were analyzed., Results: The protein level of COX-2 was significantly higher in ESCC and squamous dysplasia than in normal squamous epithelium (2.10+/-1.77 and 1.85+/-1.24 vs. 0.83+/-0.46, P<0.05). The protein level of p-Stat3 was 0 in normal squamous epithelium, 0.76+/-0.59 in squamous dysplasia, and 2.83+/-1.27 in ESCC. The protein level of p-Stat5 was 1.98+/-0.78 in normal squamous epithelium, 3.92+/-0.41 in squamous dysplasia, and 5.02+/-0.34 in ESCC. There were significant differences among the 3 groups (P<0.05). In ESCC, COX-2 expression was correlated to lymph node metastasis and differentiation (P<0.05); p-Stat3 expression was correlated to tumor invasion depth (P<0.05); but p-Stat5 expression had no correlation to clinicopathologic features. COX-2 expression was positively correlated to both p-Stat3 expression and p-Stat5 expression in ESCC., Conclusions: The up-regulation of COX-2, p-Stat3, and p-Stat5 may be correlated to the carcinogenesis of ESCC. The activation of Stat3 is correlated to the aggressive behavior of ESCC.