Aim:β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer.Recently,we detected intranuclear inclusions(NI)in hepatocellular carcinoma(HCC)containing degenerat...Aim:β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer.Recently,we detected intranuclear inclusions(NI)in hepatocellular carcinoma(HCC)containing degenerated cell organelles and lysosomal proteins and delimited by a completely closed nuclear membrane.The presence of NI was positively associated with patient survival.The aim of the current study was to investigate a possible association between proteins of the Wnt/β-catenin pathway with NI morphology and survival.Methods:We examined NI in 72 paraffin-embedded specimens of HCC.Immunohistochemistry(IHC)and immunofluorescence(IF)were performed to investigate the content and shape of NI.β-catenin gene(CTNNB1)mutations were analyzed by next generation sequencing.Results:We detected the accumulation ofβ-catenin and glutamine synthetase(a target gene ofβ-catenin)proteins within NI.Further,we found immunopositivity for the lysine demethylase KDM2A in NI.KDM2A is known to be involved inβ-catenin degradation.We detected significant associations between the presence ofβ-catenin and autophagy-associated proteins in NI.Double-IF revealed co-localization ofβ-catenin and p62 in the same NI.Kaplan-Meier survival analysis showed that the presence of NI containing KDM2A protein accumulations displayed a significant benefit in overall survival.Conclusion:We detected accumulations ofβ-catenin and proteins associated with the Wnt/β-catenin pathway partly together with autophagy-associated proteins in the same inclusion.Our finding that KDM2A immunopositivity within NIs was associated with favorable clinical outcomes and suggests a biological significance of NI.展开更多
文摘Aim:β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer.Recently,we detected intranuclear inclusions(NI)in hepatocellular carcinoma(HCC)containing degenerated cell organelles and lysosomal proteins and delimited by a completely closed nuclear membrane.The presence of NI was positively associated with patient survival.The aim of the current study was to investigate a possible association between proteins of the Wnt/β-catenin pathway with NI morphology and survival.Methods:We examined NI in 72 paraffin-embedded specimens of HCC.Immunohistochemistry(IHC)and immunofluorescence(IF)were performed to investigate the content and shape of NI.β-catenin gene(CTNNB1)mutations were analyzed by next generation sequencing.Results:We detected the accumulation ofβ-catenin and glutamine synthetase(a target gene ofβ-catenin)proteins within NI.Further,we found immunopositivity for the lysine demethylase KDM2A in NI.KDM2A is known to be involved inβ-catenin degradation.We detected significant associations between the presence ofβ-catenin and autophagy-associated proteins in NI.Double-IF revealed co-localization ofβ-catenin and p62 in the same NI.Kaplan-Meier survival analysis showed that the presence of NI containing KDM2A protein accumulations displayed a significant benefit in overall survival.Conclusion:We detected accumulations ofβ-catenin and proteins associated with the Wnt/β-catenin pathway partly together with autophagy-associated proteins in the same inclusion.Our finding that KDM2A immunopositivity within NIs was associated with favorable clinical outcomes and suggests a biological significance of NI.
