title: TRIM59 is up-regulated in gastric tumors, promoting ubiquitination and degradation of p53.
abstract: OBJECTIVE
  Little is known about factors that promote gastric carcinogenesis. We analyzed multiple microarray data sets for messenger RNAs (mRNAs) that were increased significantly in human gastric tumor samples, compared with the adjacent normal gastric tissue. We found expression of tripartite motif 59 (TRIM59), which encodes a putative ubiquitin ligase, to be increased, and investigated its effects in gastric cancer cell lines.
  
  
  METHODS
  We analyzed microarray data sets from the Oncomine database. We used quantitative polymerase chain reaction and immunoblotting to measure levels of TRIM59 mRNA and protein in 50 human gastric cancer and paired normal tissues, obtained from Renji Hospital and the First Affiliated Hospital of Nanchang University, in China. We also measured protein levels in the gastric epithelial cell line GES-1; the cancer cell lines MKN45, AGS, SGC7901, BGC823, Snu5, N87, and Snu1; and in tissue arrays of 108 human gastric tumors. TRIM59 was knocked down and overexpressed in gastric cancer cell lines, and the effects on proliferation, clone formation, migration, and growth of xenograft tumors in nude mice were assessed. TRIM59-related signaling pathways were examined by immunoblotting and quantitative polymerase chain reaction. We analyzed interactions among TRIM59, P53, and ubiquitin in immunoprecipitation studies.
  
  
  RESULTS
  Levels of TRIM59 mRNA and protein were increased significantly in gastric tumors compared with nontumor tissues; increased levels were associated with advanced tumor stage and shorter patient survival times. TRIM59 knockdown reduced proliferation, clone formation, and migration of gastric cancer cell lines, as well as growth of xenograft tumors in nude mice; overexpression of TRIM59 had the opposite effects. TRIM59 interacted physically with P53, increasing its ubiquitination and degradation. Increased levels of TRIM59 in human gastric tumors correlated with reduced expression of P53 target genes.
  
  
  CONCLUSIONS
  The putative ubiquitin ligase TRIM59 is up-regulated in human gastric tumors compared with nontumor tissues. Levels of TRIM59 correlate with tumor progression and patient survival times. TRIM59 interacts with P53, promoting its ubiquitination and degradation, and TRIM59 might promote gastric carcinogenesis via this mechanism.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhongzhong
authors.initials: Z
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: You
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: zhuhecrane@shsmu.edu.cn.
authors.forename: Helen He
authors.initials: HH
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China. Electronic address: gao.weiqiang@sjtu.edu.cn.
authors.forename: Wei-Qiang
authors.initials: WQ
authors.lastname: Gao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D000070584:Tripartite Motif Proteins; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008667:Metalloproteins; D012333:RNA, Messenger; C495901:TP53 protein, human; C530864:TRIM59 protein, human; D000070584:Tripartite Motif Proteins; D016159:Tumor Suppressor Protein p53
keywords: Oncogene; Progression; Stomach Cancer; Tumor Formation