Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas  

作　　者：Yan-Xia Wang Haibo Wu Yong Ren Shengqing Lv Chengdong Ji Dongfang Xiang Mengsi Zhang Huimin Lu Wenjuan Fu Qing Liu Zexuan Yan Qinghua Ma Jingya Miao Ruili Cai Xi Lan Bin Wu Wenying Wang Yinhua Liu Dai-Zhong Wang Mianfu Cao Zhicheng He Yu Shi Yifang Ping Xiaohong Yao Xia Zhang Peng Zhang Ji Ming Wang Yan Wang Youhong Cui Xiu-Wu Bian 

机构地区：[1]Institute of Pathology and Southwest Cancer Center,Southwest Hospital,Army Medical University(former Third Military Medical University),400038 Chongqing,China [2]Department of Pathology,The First Affiliated Hospital of University of Science and Technology of China,230036 Hefei,Anhui,China [3]Intelligent Pathology Institute,Division of Life Sciences and Medicine,University of Science and Technology of China,230036 Hefei,Anhui,China [4]Department of Pathology,General Hospital of Central Theater Command of PLA,627 Wuluo Road,Hongshan District,430070 Wuhan,Hubei,China [5]Xinqiao Hospital,Army Medical University,400038 Chongqing,China [6]Department of Pathology,The First Affiliated Hospital of Wannan Medical College,241001 Wuhu,Anhui,China [7]Department of Pathology,Taihe Hospital,Hubei University of Medicine,442000 Shiyan,Hubei,China [8]Laboratory of Cancer and Immunometabolism,Center for Cancer Research,National Cancer Institute at Frederick,Frederick,MD 21703,US

出　　处：《Signal Transduction and Targeted Therapy》2022年第4期1243-1257,共15页信号转导与靶向治疗（英文）

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).

摘　　要：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.

关 键 词：KIR2.1 invasion markedly 

分 类 号：R73[医药卫生—肿瘤]