REG Iα protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells

Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) I alpha protein, an interleukin (IL)-6-inducible gene, is suggested to be involved in the gastritis-gastric cancer sequence. We investigated the involvement of IL-6/STAT3 signaling in REG I alpha protein expression and examined whether REG I alpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG I alpha protein expression were examined using a STAT3 small interfering RNA system in gastric cancer cells. The element responsible for IL-6-induced REG I alpha promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG I alpha protein were examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling and caspase assay in vitro. Human gastric cancer specimens were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and REG I alpha protein. IL-6 treatment enhanced the expression of REG I alpha protein through STAT3 activation in gastric cancer cells. The IL-6-responsive element was determined to lie in the sequence from -142 to -134 of the REG I alpha promoter region. REG I alpha protein mediated the anti-apoptotic effects of STAT3 signaling in gastric cancer cells by enhancing Akt activation, Bad phosphorylation and Bcl-xL expression. The expression of REG I alpha protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG I alpha protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.