Studies On The Regulation Of STAT3-related Tumor Immunity By The CGAS/STING Pathway

STING(stimulator of interferon gene,also known as MITA or ERIS)is an important adaptor protein to defend pathogenic microorganism invasion in innate immunity.When cell is infected by a DNA virus,cGAMP synthase(cGAS)detects and binds the cytoplasmic DNA to produce the second messenger cGAMP.cGAMP activates the downstream molecules by binding and activating STING.Activated STING recruits and stimulates the kinase TBK1(TANK-binding kinase 1)enabling the IRF3(interferon regulatory factor 3)phosphorylation and dimerization.STING may also activates IKK(IκB kinase)and promote the NF-κB(nuclear factor κB)phosphorylation.Phosphorylation of IRF3 and NF-κB enter the nucleus and induce interferon production and related cytokine expression,which eventually lead the antiviral innate immune response to protect the body against pathogenic microorganism invasion.In normal cells,the JAK/STAT pathway plays the important role in regulation of the immune system,the production of interferonα/β will activate the JAK/STAT pathway.The activation of JAK/STAT pathway will promote cell growth and cell cycle in resist to apoptosis,which may play an important role in tumor development.STAT3 is constitutively activated in many types of tumor cells.In normal cells,IFN can also activate JAK/STAT pathway leading the activation of phosph-STAT3 involved in innate immune functions.Therefore,it needs to be addressed if the increase of phosph-STAT3-induced by IFNα-β will cause the proliferation and migration of tumor cells.We investigated the mechanism of cGAMP-induced STAT3 activation by the regulation of the cGAS/STING pathway in normal and tumor cells.The results are following:(1)L929 cells were treated with cGAMP at different hours,phosph-STAT3 activity increased in a time-dependent manner.Phosph-STAT3 was disapeared when knock out Sting or Irf3 expression in L929 cells;(2)The constitutive activation of STAT3 was detected in several human gastric cancer cells,when STIING/IRF3 pathway was activated,phosph-STAT3 was aggravated;(3)IRF3 can not be stimulated in AGS gastric cancer cells,however STAT3 was still able to be activated through NF-κB when treated with cGAMP;(4)AGS cells are more sensitive to anticancer drugs,especially the specific inhibitors of JAK/STAT3 pathway.These results provide novel clues for understanding the regulation of tumor cells by innate immunity.