Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the i...Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regulation in various cell types.3 In this study,we further reported that ZYX promoted migration,invasion,and metastasis of GC cells.Mechanistically,ZYX promoted WNK1 activation and SNAl1 up-regulation,inducing epithelial-mesenchymal transition(EMT)to enhance the mobility of GC cells.Inhibition of WNK1 impaired the mobility of GC cells.Therefore,ZYX/WNK1 could be potential therapeutic targets for GC treatment.展开更多
Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,...Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,and clinical outcomes.Unlike WNT and SHH subgroup MBs,Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options.The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity.In the present study,we demonstrate that Kir2.1,an inwardly-rectifying potassium channel,is highly expressed in non-WNT/SHH MBs,which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway.Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice.Moreover,Kir2.1^(high)/nuclear N2ICD^(high)MBs are associated with the significantly shorter lifespan of the patients.Thus,Kir2.1^(high)/nuclear N2ICD^(high)can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs.Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.展开更多
基金supported by the Chongqing Academician Program(No.cstc2019yszx-jcyjx0008 to Y.W.)The Subject of Health Commission of Hubei Province,China(No.WJ2021M222 to X.-M.W.).
文摘Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regulation in various cell types.3 In this study,we further reported that ZYX promoted migration,invasion,and metastasis of GC cells.Mechanistically,ZYX promoted WNK1 activation and SNAl1 up-regulation,inducing epithelial-mesenchymal transition(EMT)to enhance the mobility of GC cells.Inhibition of WNK1 impaired the mobility of GC cells.Therefore,ZYX/WNK1 could be potential therapeutic targets for GC treatment.
基金the National Key Research and Development Program of China(2016YFA0101203 to XW Bian and 2017YFC1309004 to Y Wang)the National Natural Science Foundation of China(31991172,81821003 to X.-W.Bian,81402080 to Y.-X.Wang)Chongqing Basic and Frontier Research Project(cstc2018jcyjAX0406 to Y.-X.Wang and cstc2018jcyjAX0168 to S.-Q.Lv).
文摘Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,and clinical outcomes.Unlike WNT and SHH subgroup MBs,Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options.The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity.In the present study,we demonstrate that Kir2.1,an inwardly-rectifying potassium channel,is highly expressed in non-WNT/SHH MBs,which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway.Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice.Moreover,Kir2.1^(high)/nuclear N2ICD^(high)MBs are associated with the significantly shorter lifespan of the patients.Thus,Kir2.1^(high)/nuclear N2ICD^(high)can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs.Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.