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The 1st Joint Session between JDDW & KDDW & TDDW 5 (JDDW)
Thu. October 12th   15:00 - 16:00   Room 8: Fukuoka International Congress Center 411+412
Inhibition of STAT3 in gastric cancer; Role of Pantoprazole as SHP-1 inducer
M. K. Joo
Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine, Guro Hospital
The biologic impact of janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) axis in gastric cancer has been well established. Phosphorylated STAT3 dimerize and act as a transcription factor to upregulate various target genes involving tumor invasion and epithelial-mesenchymal transition (EMT). Furthermore, JAK2/STAT3 signaling mediates core interaction between cancer cells and microenvironmental immune system. Thus, inhibition of STAT3 signaling is considered as a crucial issue for the control of gastric carcinogenesis and invasion. Unfortunately, few drugs to directly inhibit STAT3 signaling have been introduced and clinically tried in gastric cancer patients. We have investigated the indirect pathway to inactivate STAT3 signaling via dephosphorylation, and focused on the role of SH2-containing protein tyrosine phosphatase 1 (SHP-1), which has not been extensively studied gastric cancer research field. We found that protein and gene expression of SHP-1 were minimal or abolished in gastric cancer cell lines, and transfection of SHP-1 plasmid in gastric cancer cells effectively downregulated phosphorylated STAT3 and inhibited cellular invasion and EMT. We also found that pantoprazole, a proton pump inhibitor which inhibits acid secretion in gastric parietal cells, significantly enhanced SHP-1 expression in gastric cancer cells. This, in turn, downregulated p-STAT3 activity and downstream EMT process, which could be validated in vivo xenograft tumor model. Taken together, we suggest that SHP-1 is an important mediator to inactive STAT3 signaling in gastric cancer, and a discovery of effective compound which can induce SHP-1 expression might be valuable for an alternative therapeutic option of gastric cancer.
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