Differential roles of STAT3 depending on the mechanism of STAT3 activation in gastric cancer cells

Abstract

Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated in response to growth factors and cytokines, and which contributes to the regulation of cell proliferation, apoptosis, and motility in many human tumour types.Methods:We investigated the mechanisms of STAT3 activation and the function of STAT3 depending on its mechanism of activation in gastric cancer cells.Results:The MET-tyrosine kinase inhibitor (TKI) and cell transfection with a small interfering RNA (siRNA) specific for MET mRNA inhibited STAT3 phosphorylation in MET-activated cells, indicating that STAT3 activation is linked to MET signalling. Forced expression of a constitutively active form of STAT3 also attenuated MET-TKI-induced apoptosis, suggesting that inhibition of STAT3 activity contributes to MET-TKI-induced apoptosis. MKN1 and MKN7 cells, both of which are negative for MET activation, produced interleukin-6 (IL-6) that activated STAT3 through the Janus kinase pathway. Depletion of STAT3 by siRNA inhibited migration and invasion of these cells, suggesting that STAT3 activated by IL-6 contributes to regulation of cell motility. Conclusion: Our data thus show that activated STAT3 contributes to either cell survival or motility in gastric cancer cells, and that these actions are related to different mechanisms of STAT3 activation. © 2011 Cancer Research UK All rights reserved.