CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer
- Shouyu Wang1,
- Xuming Wu1,2,
- Jianbing Zhang1,2,
- Yansu Chen1,
- Jin Xu1,
- Xiaowei Xia1,
- Song He2,
- Fulin Qiang2,
- Aiping Li1,
- Yongqian Shu3,
- Oluf Dimitri Røe4,5,
- Gang Li6,
- Jianwei W Zhou1
- 1Department 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, People's Republic of China
- 2Department of Pathology, Nantong Cancer Hospital, Nantong, People's Republic of China
- 3Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- 4Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- 5Cancer Clinic, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway
- 6Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, Canada
- Correspondence to Professor J Zhou, 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;
Contributors SW, XW, JZ, YC, JX and AL performed the experiments; SW, YC and XX analysed the data; SH and FQ provided the samples; SW and JWZ wrote the paper; YS, ODR and GL commented on the study and revised the paper; JWZ designed the research.
- Revised 6 March 2012
- Accepted 8 March 2012
- Published Online First 25 April 2012
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.
Funding This study was supported in part by the project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, the National Natural Science Foundation of China (30930080, 81161120537 to JWZ, 81001231 to SW) and the Postdoctoral Science Foundation of China (20100481165 to SW).
Competing interests None.
Ethics approval The use of human gastric cancer tissues and the waiver of patient consent in this study were approved by the Clinical Research Ethics Board of the Nantong Cancer Hospital and the Ethics Committee of the Nanjing Medical University, respectively. The study was conducted according to the principles expressed in the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.