The ability to harness innate immunity is a promising solution for improving cancer immunotherapy.Interferon(IFN)induces expression of IFN-stimulated genes(ISGs)by activating the JAK-STAT signaling pathway to promote ...The ability to harness innate immunity is a promising solution for improving cancer immunotherapy.Interferon(IFN)induces expression of IFN-stimulated genes(ISGs)by activating the JAK-STAT signaling pathway to promote innate immunity and inhibit malignant tumor growth,but the functions and mechanisms of most ISGs in cancer regulation are unknown.As an innate immune effector,ISG12a promotes the innate immune response to viral infection.In this study,ISG12a was found to be expressed at low levels in gastrointestinal cancer,represented by hepatocellular cancer(HCC)and gastric cancer(GC),and it identified as a tumor suppressor that affects clinical prognosis.ISG12a silencing accelerated the malignant transformation and epithelial–mesenchymal transition of cancer cells.Mechanistically,ISG12a promotedβ-catenin proteasomal degradation by inhibiting the degradation of ubiquitinated Axin,thereby suppressing the canonical Wnt/β-catenin signaling pathway.Notably,β-catenin was identified as a transcription factor for PD-L1.Inhibition of Wnt/β-catenin signaling by ISG12a suppressed expression of the immune checkpoint PDL1,rendering cancer cells sensitive to NK cell-mediated killing.This study reveals a mechanism underlying the anticancer effects of IFN.Some ISGs,as represented by ISG12a,may be useful in cancer therapy and prevention.The identified interrelations among innate immunity,Wnt/β-catenin signaling,and cancer immunity may provide new insight into strategies that will improve the efficiency of immunotherapy.展开更多
基金supported by grants from the National Natural Science Foundation of China(81730064 and 81571985 to H.Z.)National Science and Technology Major Project(2017ZX10202201 and 2009ZX10004-312 to H.Z.)+2 种基金National Natural Science Foundation of China(81601383 to S.T.,31571368 and 31871324 to G.L.,81902069 to B.X.)China Postdoctoral Science Foundation(2019M652760 to B.X.)Hunan Natural Science Foundation(2018JJ3090 to H.Z.,2018JJ3091 to S.T.,2018JJ3713 and 2018RS3006 to G.L.).
文摘The ability to harness innate immunity is a promising solution for improving cancer immunotherapy.Interferon(IFN)induces expression of IFN-stimulated genes(ISGs)by activating the JAK-STAT signaling pathway to promote innate immunity and inhibit malignant tumor growth,but the functions and mechanisms of most ISGs in cancer regulation are unknown.As an innate immune effector,ISG12a promotes the innate immune response to viral infection.In this study,ISG12a was found to be expressed at low levels in gastrointestinal cancer,represented by hepatocellular cancer(HCC)and gastric cancer(GC),and it identified as a tumor suppressor that affects clinical prognosis.ISG12a silencing accelerated the malignant transformation and epithelial–mesenchymal transition of cancer cells.Mechanistically,ISG12a promotedβ-catenin proteasomal degradation by inhibiting the degradation of ubiquitinated Axin,thereby suppressing the canonical Wnt/β-catenin signaling pathway.Notably,β-catenin was identified as a transcription factor for PD-L1.Inhibition of Wnt/β-catenin signaling by ISG12a suppressed expression of the immune checkpoint PDL1,rendering cancer cells sensitive to NK cell-mediated killing.This study reveals a mechanism underlying the anticancer effects of IFN.Some ISGs,as represented by ISG12a,may be useful in cancer therapy and prevention.The identified interrelations among innate immunity,Wnt/β-catenin signaling,and cancer immunity may provide new insight into strategies that will improve the efficiency of immunotherapy.
