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Original article
Vitamin D3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice
  1. Hyo-Jung Kwon1,2,
  2. Young-Suk Won1,
  3. Ki-Taek Nam3,
  4. Yeo-Dae Yoon4,
  5. Hyang Jee2,
  6. Won-Kee Yoon1,
  7. Ki-Hoan Nam1,
  8. Jong-Soon Kang4,
  9. Sang-Uk Han5,
  10. In-Pyo Choi6,
  11. Dae-Yong Kim2,
  12. Hyoung-Chin Kim1
  1. 1Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea
  2. 2Department of Veterinary Pathology and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
  3. 3Nashville VA Medical Center and the Departments of Surgery and Cell and Developmental Biology, Epithelial Biology Center, Nashville, Tennessee, USA
  4. 4Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea
  5. 5Department of Surgery, College of Medicine, Ajou University, Suwon, Republic of Korea
  6. 6Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Taejon, Republic of Korea
  1. 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

Abstract

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 (TNFα) level, nuclear transcription factor kappa B (NF-κB) activation and cyclooxygenase-2 (COX-2) expression. An in vitro study showed that H pylori-associated cell proliferation and induction of TNFα, NF-κB and COX-2 were inhibited in cells transfected with VDUP1. In addition, overexpression of VDUP1 in AGS cells suppressed TNFα-induced NF-κB 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 TNFα, NF-κB and COX-2. These findings provide important insights into the role of VDUP1 in H pylori-associated tumourigenesis.

  • H pylori
  • COX-2
  • NF-κB
  • TNFα
  • VDUP1
  • gastric cancer
  • gastrointestinal cancer
  • molecular pathology
  • stem cells

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Footnotes

  • See Commentary, p 2

  • DYK and HCK contributed equally to this work as corresponding authors.

  • Funding This study was supported by a grant from the National Research Foundation of Korea (0020879) and the New Drug Target Discovery Project (M10848000352-08N4800-35210), the Ministry of Education, Science and Technology, Republic of Korea.

  • Competing interests None.

  • Ethics approval We used commercial tissue array slides (SuperBioChips Laboratories, Seoul, Korea).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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