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. For example, activated STAT3 in gastric epithelial cells by Helicobacter pylori (H. pylori)-induced cytotoxin-associated antigen (CagA) modulates differentiation of Thelper (Th)-17 lineage to promote chronic mucosal inflammation, atrophy and intestinal metaplasia. 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 several agents including natural compounds enhanced SHP-1 expression in SHP-1-negative gastric cancer cells. 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.
|Title of host publication||Advances in Carcinogenesis Research|
|Publisher||Nova Science Publishers, Inc.|
|Number of pages||20|
|Publication status||Published - 2016 Jan 1|
- Gastric cancer
ASJC Scopus subject areas