title: CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer.
abstract: OBJECTIVE
  CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC).
  
  
  METHODS
  The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo.
  
  
  RESULTS
  CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis.
  
  
  CONCLUSIONS
  Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.
authors.affiliation: Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Centre, School of Public Health, Nanjing Medical University, Nanjing 210029, People's Republic of China.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Wang
authors.forename: Xuming
authors.initials: X
authors.lastname: Wu
authors.forename: Jianbing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yansu
authors.initials: Y
authors.lastname: Chen
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xia
authors.forename: Song
authors.initials: S
authors.lastname: He
authors.forename: Fulin
authors.initials: F
authors.lastname: Qiang
authors.forename: Aiping
authors.initials: A
authors.lastname: Li
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
authors.forename: Oluf Dimitri
authors.initials: OD
authors.lastname: Røe
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Jianwei W
authors.initials: JW
authors.lastname: Zhou
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002470:Cell Survival; D019175:DNA Methylation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013274:Stomach Neoplasms / Q000378:metabolism*; D016019:Survival Analysis; D046888:Tissue Array Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D016209:Interleukin-8; D016328:NF-kappa B; D008156:Luciferases; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases