Vitamin D3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice
Hyo-Jung Kwon 1,2, Young-Suk Won 1, Ki-Taek Nam 3, Yeo-Dae Yoon 4, Hyang Jee 2, Won-Kee Yoon 1, Ki-Hoan Nam 1,
Jong-Soon Kang 4, Sang-Uk Han 5, In-Pyo Choi 6, Dae-Yong Kim 2, Hyoung-Chin Kim 1
1 Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea
2 Department of Veterinary Pathology and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
3 Nashville VA Medical Center and the Departments of Surgery and Cell and Developmental Biology, Epithelial Biology Center, Nashville, Tennessee, USA
4 Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea
5 Department of Surgery, College of Medicine, Ajou University, Suwon, Republic of Korea
6 Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Taejon, Republic of Korea
Correspondence to Dr Hyoung-Chin Kim, Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, 685-1, Yangcheong-ri, Ochang-eup, Chungbuk 363-883, Korea; hckim at kribb.re.kr
Contributors HJ Kwun and YS Won: conception, design, analysis and interpretation of data, drafting of the manuscript, critical revision of article, final approval given. KT Nam, YD Yoon and H Jee: conception, design, analysis and interpretation of data, final approval given. WK Yoon, KH Nam, JS Kang, SU Han and IP Choi: conception, design, drafting of the manuscript, critical revision of article, final approval given. DY Kim and HC Kim: conception, design, analysis and interpretation of data, drafting of the manuscript, critical revision of article, final approval given.
Revised 20 July 2011, Accepted 4 August 2011, Published Online First 13 September 2011
Objective Vitamin D3 upregulated protein 1 (VDUP1) is a potent tumour suppressor whose expression is dramatically reduced in various types of human cancers, including gastric cancer. However, the precise mechanisms underlying tumour development remain unclear. In the present study, the authors examined the effect of VDUP1 on Helicobacter pylori-induced gastric carcinogenesis in mice.
Design Gastric cancer was generated in VDUP1 knockout (KO) and wild-type mice using a combination of N-methyl-N-nitrosourea treatment and H pylori infection. Fifty weeks after treatment, gastric tissues from both types of mice were examined by histopathology, immunohistochemistry and immunoblotting. In vitro tests on the human gastric cancer cell line, AGS, were also performed to identify the underlying mechanisms of cancer development.
Results The overall incidence of gastric cancer was significantly higher in VDUP1 KO mice than in wild-type mice. Similarly, VDUP1 KO mice showed more severe chronic gastritis, glandular atrophy, foveolar hyperplasia, metaplasia and dysplasia. Although no differences in the apoptotic index were apparent, lack of VDUP1 increased the rate of gastric epithelial cell proliferation in non-cancerous stomachs, with corresponding increases in tumour necrosis factor alpha (TNF?) level, nuclear transcription factor kappa B (NF-?B) activation and cyclooxygenase-2 (COX-2) expression. An in vitro study showed that H pylori-associated cell proliferation and induction of TNF?, NF-?B and COX-2 were inhibited in cells transfected with VDUP1. In addition, overexpression of VDUP1 in AGS cells suppressed TNF?-induced NF-?B activation and COX-2 expression.
Conclusion Our data show that VDUP1 negatively regulates H pylori-associated gastric carcinogenesis, in part by disrupting cell growth and inhibiting the induction of TNF?, NF-?B and COX-2. These findings provide important insights into the role of VDUP1 in H pylori-associated tumourigenesis.
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