title: USP22 promotes NSCLC tumorigenesis via MDMX up-regulation and subsequent p53 inhibition.
abstract: Increasing evidence suggests that ubiquitin-specific protease 22 (USP22) has great clinicopathologic significance in oncology. In this study, we investigated the role of USP22 in human NSCLC tumorigenesis along with the underlying mechanisms of action. First, we determined the expression of USP22 in human NSCLC, as well as normal tissues and cell lines. We then studied the effects of USP22 silencing by shRNA on NSCLC cell growth in vitro and tumorigenesis in vivo, along with the effect on the p53 pathway. We found that USP22 is overexpressed in human NSCLC tissues and cell lines. USP22 silencing by shRNA inhibits proliferation, induces apoptosis and arrests cells at the G0/G1 phases in NSCLC cells and curbs human NSCLC tumor growth in a mouse xenograft model. Additionally, USP22 silencing downregulates MDMX protein expression and activates the p53 pathway. Our co-immunoprecipitation analysis shows that USP22 interacts with MDMX in NSCLC cells. Furthermore, MDMX silencing leads to growth arrest and apoptosis in NSCLC cells, and over-expression of MDMX reverses the USP22 silencing-induced effects. Taken together, our results suggest that USP22 promotes NSCLC tumorigenesis in vitro and in vivo through MDMX upregulation and subsequent p53 inhibition. USP22 may represent a novel target for NSCLC treatment.
authors.affiliation: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China. drnail@sina.com.
authors.forename: Fangbao
authors.initials: F
authors.lastname: Ding
authors.affiliation: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China. bcrcar@126.com.
authors.forename: Chunrong
authors.initials: C
authors.lastname: Bao
authors.affiliation: Institute of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, China. tyuecar@126.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China. xbcardio@163.com.
authors.forename: Haibo
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China. wmso126@126.com.
authors.forename: Mingsong
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China. xixe126@126.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China. hqng126@126.com.
authors.forename: Fengqing
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China. mju126@126.com.
authors.forename: Ju
authors.initials: J
authors.lastname: Mei
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human