A novel p38‐MAPK signaling axis modulates neutrophil biology in head and neck cancer

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: p27;    CREB;    inflammation;    CCL4;    MMP9;   

DOI  :  10.1189/jlb.0411193

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Neutrophilsareemergingasimportantmediatorsincancerprogression.RecentstudiesassociatedneutrophilswithpoorclinicaloutcomeofHNCpatientsandshowedthatHNCinducesrecruitment,survival,andreleaseofproinflammatoryfactorsbyneutrophilsinvitro.ThemolecularmechanismsthroughwhichHNCandothercancersmodulateneutrophilbiologyarecurrentlyunknown.Toexplorethesemechanisms,weusedaninvitrosystemthatmodelstheinteractionbetweenhumanHNCcellsandneutrophilsorneutrophilic‐differentiatedHL‐60cells,respectively.WeshowthatHNC‐derivedfactorsactivatep38‐MAPKinneutrophils,whichpartlypromotesneutrophilsurvival,butnotneutrophilrecruitmentandmotility.Mostimportantly,HNC‐inducedp38‐MAPKactivationstronglystimulatesthereleaseofCCL4,CXCL8,andMMP9byneutrophils.WeidentifyCREBandinterestingly,p27phosphorylatedatT198asdownstreammembersoftheHNC‐inducedp38‐MAPKsignalingcascade.UsingsiRNAtechnology,wedemonstratethatp27andCREBmediatethereleaseofCCL4andCXCL8andthatCREB,additionally,mediatesthereleaseofMMP9.Thesedataunravelnovelmolecularmechanismsinvolvedinregulationofneutrophilproinflammatoryfunctions.OurstudiesonhumanHNCtissuesindicatethattumor‐infiltratingneutrophilsmightbeamajorsourceofCCL4andparticularly,MMP9incancerpatients.Thus,ourfindingsprovidenovel,mechanisticinsightsrelevantforthepathophysiologyofHNCandpossibly,othertypesofcanceraswell...

【 授权许可】

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