More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1(YAP1) and its close paralog TAZ,...More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1(YAP1) and its close paralog TAZ, transcriptional co-activator with a PDZbinding motif, function as key effectors negatively controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In various cancers, Hippo pathway cross-talks with pro- or anti-tumorigenic pathways such as GPCR, Wnt/β-catenin, Notch and TGF-β signaling and is deregulated by multiple factors including cell density/junction and micro RNAs. As YAP1 expression is significantly associated with poor prognosis of gastric and other gastrointestinal cancers, detailed delineation of Hippo regulation in tumorigenesis provides novel insight for therapeutic intervention. In current review, we summarized the recent research progresses on the deregulation of Hippo pathway in the gastrointestinal tract including stomach and discuss the molecular consequences leading to tumorigenesis.展开更多
Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic...Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic and non-genetic determinants of ferroptosis.Hippo signaling pathway is an evolutionarily conserved pathway that responds to various envi-ronmental cues and controls organ size,cell proliferation,death,and self-renewal capacity.In cancer biology,Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion,cancer development,metastasis,and treatment resistance.Hippo dysregulation leads to aberrant activation of YAP and TAZ,the two major transcription co-activators of TEADs,that induce the expression of genes triggering tumor-promoting pheno-types,including enhanced cell proliferation,self-renewal and apoptosis inhibition.The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence.Recently,fer-roptosis has also been found being regulated by the cellular contact and density.The YAP/TAZ activation under low density,while confers apoptosis resistance,renders cancer cells sensitivity to ferroptosis.These findings establish YAP/TAZ and Hippo pathways as novel deter-minants of ferroptosis.Therefore,inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells.Reciprocally,various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance,limiting the therapeutic efficacy.展开更多
基金General Research Fund(No.2140855RGC Reference No.CUHK14114414)from The Research Grants Council of Hong Kong+1 种基金National Natural Science Grant No.81201591 from ChinaDirect Grant for Research No.2014.2.002 from The Chinese University of Hong Kong
文摘More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1(YAP1) and its close paralog TAZ, transcriptional co-activator with a PDZbinding motif, function as key effectors negatively controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In various cancers, Hippo pathway cross-talks with pro- or anti-tumorigenic pathways such as GPCR, Wnt/β-catenin, Notch and TGF-β signaling and is deregulated by multiple factors including cell density/junction and micro RNAs. As YAP1 expression is significantly associated with poor prognosis of gastric and other gastrointestinal cancers, detailed delineation of Hippo regulation in tumorigenesis provides novel insight for therapeutic intervention. In current review, we summarized the recent research progresses on the deregulation of Hippo pathway in the gastrointestinal tract including stomach and discuss the molecular consequences leading to tumorigenesis.
基金support from the members of the Chilab.We acknowledge the financial support in part by DOD(grant numbers W81XWH-17-1-0143,W81XWH-15-1-0486,W81XWH-19-1-0842)NIH(grant numbers GM124062,1R01NS111588-01A1).
文摘Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic and non-genetic determinants of ferroptosis.Hippo signaling pathway is an evolutionarily conserved pathway that responds to various envi-ronmental cues and controls organ size,cell proliferation,death,and self-renewal capacity.In cancer biology,Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion,cancer development,metastasis,and treatment resistance.Hippo dysregulation leads to aberrant activation of YAP and TAZ,the two major transcription co-activators of TEADs,that induce the expression of genes triggering tumor-promoting pheno-types,including enhanced cell proliferation,self-renewal and apoptosis inhibition.The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence.Recently,fer-roptosis has also been found being regulated by the cellular contact and density.The YAP/TAZ activation under low density,while confers apoptosis resistance,renders cancer cells sensitivity to ferroptosis.These findings establish YAP/TAZ and Hippo pathways as novel deter-minants of ferroptosis.Therefore,inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells.Reciprocally,various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance,limiting the therapeutic efficacy.
