RING finger 138 deregulation distorts NF-κB signaling and facilities colitis switch to aggressive malignancy  

作　　者：Yalan Lu Rong Huang Jianming Ying Xingchen Li Tao Jiao Lei Guo Haitao Zhou Han Wang Amannisa Tuersuntuoheti Jianmei Liu Qichen Chen Yanhong Wang Luying Su Changyuan Guo Fu Xu Ziyi Wang Yan Lu Kai Li Junbo Liang Zhen Huang Xiao Chen Jinjie Yao Hanjie Hu Xiaowen Cheng Yufeng Wan Xinyan Chen Ning Zhang Shiying Miao Jianqiang Cai Linfang Wang Changzheng Liu Wei Song Hong Zhao 

机构地区：[1]Department of Biochemistry and Molecular Biology,State Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College,Beijing 100005,China [2]Department of Hepatobiliary Surgery,State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [3]Key Laboratory of Gene Editing Screening and R&D of Digestive System Tumor Drugs,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [4]Key Laboratory of Human Disease Comparative Medicine,Chinese Ministry of Health,Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases,Institute of Laboratory Animal Science,Chinese Academy of Medical Sciences and Comparative Medicine Center,Peking Union Medical College,Beijing 100021,China [5]National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Shenzhen 518116,China [6]Department of Pathology,State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [7]Department of Clinical Laboratory,the First Affiliated Hospital,Anhui Medical University,Hefei 230022,China [8]Wellcome Centre for Anti-Infectives Research(WCAIR),Division of Biological Chemistry and Drug Discovery,School of Life Sciences,University of Dundee,Dundee DD15EH,UK

出　　处：《Signal Transduction and Targeted Therapy》2022年第7期2555-2567,共13页信号转导与靶向治疗（英文）

基　　金：supported by CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-066,2017-I2M-4-002 to H.Z.,2021-I2M-1-019 to W.S.,2021-1-I2M-014 to C.Z.L.);the National Natural Science Foundation of China(81972311,82141127 and 81672461 to H.Z.,81672472,and 31970794 to W.S.,81570780 to C.Z.L.,32000586 to K.L.);the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT310026 to H.Z.);Sanming Project of Medicine in Shenzhen(SZSM202011010 to H.Z.);the National Key Research and Development Program of China(2018YFC1003500 to W.S.);the State Key Laboratory Special fund from the Ministry of Science(2060204 to W.S.);the State Key Project on Infection Diseases of China(2017ZX10201021-007-003 to H.Z.).

摘　　要：Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction.Here,we discovered the critical role of RING finger 138(RNF138)in CRC tumorigenesis through regulating the NF-кB signaling,which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response.RNF138^(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy,which coincided with sustained aberrant NF-кB signaling in the colonic cells.Furthermore,RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein(NIBP)to the cytoplasm,which requires the ubiquitin interaction motif(UIM)domain.More importantly,we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings,raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling.Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients,we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth.Overall,our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression,and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.

关 键 词：MALIGNANCY SUSTAINED FINGER 

分 类 号：R73[医药卫生—肿瘤]