Increased expression of hepcidin and associated upregulation of JAK/STAT3 signaling in human gastric cancer

Abstract

Gastric cancer is one of the most common malignancies with high cancer-associated mortality rate globally. Hepcidin is the peptide hormone, which is critically important in the regulation of systemic iron homeostasis. Cumulating evidence has reported that the disturbed local expression of hepcidin may serve as a predictive biomarker in assessing the clinical outcomes in a range of cancer types. However, the expression profile of hepcidin in human gastric cancer is remains to be investigated. In the present retrospective study, using archived paraffin-embedded tissue blocks, the local production of hepcidin by immunohistochemical analysis was detected, and then its correlation with clinicopathological characteristics in human gastric cancer was evaluated. In parallel, using western blotting, quantitative reverse transcription polymerase chain reaction and chromatin immunoprecipitation assay, the local status of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling in response to inflammatory stimuli mediated by interleukin (IL)-6, which in turn regulates transcriptional activity of hepcidin gene (HAMP) was also assessed. The results indicated that, the local production of hepcidin was significantly elevated in tumor tissues compared with adjacent non-tumor tissues, and was tightly correlated with increasing tumor stages according to the tumor node metastasis (TNM) classification. In addition, JAK/STAT3 signaling and the STAT3 binding affinity to the HAMP gene promoter were significantly enhanced, in parallel with an increased expression of hepcidin, in tumor tissues compared with adjacent non-tumor tissues. Collectively, the present study indicated that local expression of hepcidin in gastric cancer tumor tissues was positively correlated with increasing tumor stages, which may be closely associated with the upregulation of IL-6-mediated JAK/STAT3 signaling in human gastric cancer.