Abstract
Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) (n = 116) or squamous cell carcinoma (SCC) (n = 38) tumours. The tissues were stained for pSTAT3 and IL-6R using immunohistochemistry. The OE33 (OAC) and OE21 (SCC) cell lines were treated with the STAT3 inhibitor, STATTIC. The Univariate cox regression analysis revealed that a positive pSTAT3 in SCC was adversely associated with survival (Hazard ratio (HR) 6.382, 95% CI 1.266–32.184), while a protective effect was demonstrated with the higher pSTAT3 levels in OAC epithelium (HR 0.74, 95% CI 0.574–0.953). The IL-6R intensity levels were higher in the SCC tumours compared with the OAC tumours for the core and leading edge tumour tissue. The pSTAT3 levels correlated positively with the IL-6R levels in both the OAC and SCC. The treatment of OE21 and OE33 cells with the STAT3 inhibitor STATTIC in vitro resulted in decreased survival, proliferation, migration, and increased apoptosis. The pSTAT3 expression was associated with adverse survival in SCC, but not in the OAC patients. The inhibition of STAT3 in both of the tumour subtypes resulted in alterations in the survival, proliferation, migration, and apoptosis, suggesting a potential role for therapeutically targeting STAT3.
Highlights
Oesophageal cancer is the eighth most common malignancy worldwide and the sixth leading cause of cancer-related deaths [1]
We demonstrated that the elevated levels of pSTAT3 were associated with poorer survival in oesophageal squamous cell carcinoma (SCC), with the inverse having been identified for pSTAT3 in the oesophageal adenocarcinoma (OAC) tumours
We have shown in this study that OAC and SCC exhibit divergent STAT3 expression patterns
Summary
Oesophageal cancer is the eighth most common malignancy worldwide and the sixth leading cause of cancer-related deaths [1]. The phosphorylation of receptors results in STAT protein recruitment, phosphorylation, and dimerisation This results in nuclear translocation and transcriptional control via DNA binding, to target the gene regulatory sequences [6]. Gene targets include cyclin B1, cyclin D1/2, cdc, and c-myc, whose transcriptional upregulation results in progression through the G1/S phase of the cell cycle. Another group of STAT3 targets the genes that induce VEGF and HIF1-α induced angiogenesis. This results in tumour revascularization [7], while MMP2 and MMP9 facilitate with the tumour metastasis [7]. The cytokines implicated in the activation of STAT3 signaling include oncostatin M (OSM), interleukin-6 (IL-6), and Leptin [8,9,10]
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