Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significa...Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC.Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network.Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein(YAP) and WW-domaincontaining transcriptional co-activator with PDZ-binding motif(TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.展开更多
目的检测肾癌组织Yes相关蛋白1(Yes-associated protein 1,YAP1),PDZ结合域的转录共刺激因子(transcriptional coactivator with PDZ-binding motif,TAZ)蛋白表达,并探讨其与临床病理特征及患者远期生存的关系。方法前瞻性选取安徽医科...目的检测肾癌组织Yes相关蛋白1(Yes-associated protein 1,YAP1),PDZ结合域的转录共刺激因子(transcriptional coactivator with PDZ-binding motif,TAZ)蛋白表达,并探讨其与临床病理特征及患者远期生存的关系。方法前瞻性选取安徽医科大学第二附属医院2016年1月~2018年10月收治的132例肾癌患者。根据三年内是否死亡将其分为死亡组(n=20)和生存组(n=108)。采用免疫组织化学二步法检测YAP1,TAZ蛋白表达,用COX回归分析探讨患者死亡的危险因素。结果手术组切缘正常组织YAP1,TAZ蛋白阳性表达率分别为22.41%和17.24%,癌组织YAP1,TAZ蛋白阳性表达率分别为53.45%和48.28%,对应癌组织高于切缘正常组织(χ^(2)=11.864,12.680,P=0.001,0.000)。穿刺活检癌组织YAP1和TAZ蛋白阳性表达率分别为77.14%和62.86%。临床分期、有副肿瘤综合征、有远处转移、伴下腔静脉癌栓、组织学分级与癌组织YAP1蛋白阳性表达率均呈正相关(χ^(2)=8.664~21.321,P=0.000~0.003),与TAZ蛋白阳性表达率也呈正相关(χ^(2)=6.518~25.529,P=0.000~0.001);癌组织YAP1,TAZ蛋白阳性表达与肾癌三年内生存率均呈正相关(χ^(2)=10.273,12.657;P=0.001,0.000);临床分期Ⅲ~Ⅳ期[风险比(hazard ratio,HR)=3.550,P=0.016]、有副肿瘤综合征(HR=4.267,P=0.012)、组织学Ⅲ~Ⅳ级(HR=5.382,P=0.001)、癌组织TAZ蛋白阳性表达(HR=5.760,P=0.007)、伴下腔静脉癌栓(HR=6.508,P=0.005)、有远处转移(HR=7.330,P=0.003)、癌组织YAP1蛋白阳性表达(HR=7.877,P=0.001)均是肾癌三年内死亡的危险因素。结论肾癌组织YAP1和TAZ蛋白阳性表达率高,且与临床分期、组织学分级、副肿瘤综合征、远处转移和下腔静脉癌栓有关,上述病理特征与癌组织YAP1和TAZ蛋白阳性表达均是患者远期生存的影响因素。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
文摘Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC.Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network.Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein(YAP) and WW-domaincontaining transcriptional co-activator with PDZ-binding motif(TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.
文摘目的检测肾癌组织Yes相关蛋白1(Yes-associated protein 1,YAP1),PDZ结合域的转录共刺激因子(transcriptional coactivator with PDZ-binding motif,TAZ)蛋白表达,并探讨其与临床病理特征及患者远期生存的关系。方法前瞻性选取安徽医科大学第二附属医院2016年1月~2018年10月收治的132例肾癌患者。根据三年内是否死亡将其分为死亡组(n=20)和生存组(n=108)。采用免疫组织化学二步法检测YAP1,TAZ蛋白表达,用COX回归分析探讨患者死亡的危险因素。结果手术组切缘正常组织YAP1,TAZ蛋白阳性表达率分别为22.41%和17.24%,癌组织YAP1,TAZ蛋白阳性表达率分别为53.45%和48.28%,对应癌组织高于切缘正常组织(χ^(2)=11.864,12.680,P=0.001,0.000)。穿刺活检癌组织YAP1和TAZ蛋白阳性表达率分别为77.14%和62.86%。临床分期、有副肿瘤综合征、有远处转移、伴下腔静脉癌栓、组织学分级与癌组织YAP1蛋白阳性表达率均呈正相关(χ^(2)=8.664~21.321,P=0.000~0.003),与TAZ蛋白阳性表达率也呈正相关(χ^(2)=6.518~25.529,P=0.000~0.001);癌组织YAP1,TAZ蛋白阳性表达与肾癌三年内生存率均呈正相关(χ^(2)=10.273,12.657;P=0.001,0.000);临床分期Ⅲ~Ⅳ期[风险比(hazard ratio,HR)=3.550,P=0.016]、有副肿瘤综合征(HR=4.267,P=0.012)、组织学Ⅲ~Ⅳ级(HR=5.382,P=0.001)、癌组织TAZ蛋白阳性表达(HR=5.760,P=0.007)、伴下腔静脉癌栓(HR=6.508,P=0.005)、有远处转移(HR=7.330,P=0.003)、癌组织YAP1蛋白阳性表达(HR=7.877,P=0.001)均是肾癌三年内死亡的危险因素。结论肾癌组织YAP1和TAZ蛋白阳性表达率高,且与临床分期、组织学分级、副肿瘤综合征、远处转移和下腔静脉癌栓有关,上述病理特征与癌组织YAP1和TAZ蛋白阳性表达均是患者远期生存的影响因素。
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.
