Vitamin D 3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice

Hyo Jung Kwon, Young Suk Won, KiTaek Nam, Yeo Dae Yoon, Hyang Jee, Won Kee Yoon, Ki Hoan Nam, Jong Soon Kang, Sang Uk Han, In Pyo Choi, Dae Yong Kim, Hyoung Chin Kim

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Objective: Vitamin D 3 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 noncancerous 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-βB 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 pyloriassociated tumourigenesis.

Original languageEnglish
Pages (from-to)53-63
Number of pages11
JournalGut
Volume61
Issue number1
DOIs
Publication statusPublished - 2012 Jan 1

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Methylnitrosourea
Protein Deficiency
Cholecalciferol
Helicobacter pylori
Stomach
Carcinogenesis
Stomach Neoplasms
Cyclooxygenase 2
Proteins
Pylorus
Tumor Necrosis Factor-alpha
Knockout Mice
Cell Proliferation
Neoplasms
NF-kappa B
Metaplasia
Gastritis
Immunoblotting
Atrophy
Hyperplasia

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Kwon, Hyo Jung ; Won, Young Suk ; Nam, KiTaek ; Yoon, Yeo Dae ; Jee, Hyang ; Yoon, Won Kee ; Nam, Ki Hoan ; Kang, Jong Soon ; Han, Sang Uk ; Choi, In Pyo ; Kim, Dae Yong ; Kim, Hyoung Chin. / Vitamin D 3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice. In: Gut. 2012 ; Vol. 61, No. 1. pp. 53-63.
@article{c47c53f2fd6840baa198a42ebb9aa254,
title = "Vitamin D 3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice",
abstract = "Objective: Vitamin D 3 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 noncancerous 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-βB 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 pyloriassociated tumourigenesis.",
author = "Kwon, {Hyo Jung} and Won, {Young Suk} and KiTaek Nam and Yoon, {Yeo Dae} and Hyang Jee and Yoon, {Won Kee} and Nam, {Ki Hoan} and Kang, {Jong Soon} and Han, {Sang Uk} and Choi, {In Pyo} and Kim, {Dae Yong} and Kim, {Hyoung Chin}",
year = "2012",
month = "1",
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Kwon, HJ, Won, YS, Nam, K, Yoon, YD, Jee, H, Yoon, WK, Nam, KH, Kang, JS, Han, SU, Choi, IP, Kim, DY & Kim, HC 2012, 'Vitamin D 3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice', Gut, vol. 61, no. 1, pp. 53-63. https://doi.org/10.1136/gutjnl-2011-300361

Vitamin D 3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice. / Kwon, Hyo Jung; Won, Young Suk; Nam, KiTaek; Yoon, Yeo Dae; Jee, Hyang; Yoon, Won Kee; Nam, Ki Hoan; Kang, Jong Soon; Han, Sang Uk; Choi, In Pyo; Kim, Dae Yong; Kim, Hyoung Chin.

In: Gut, Vol. 61, No. 1, 01.01.2012, p. 53-63.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Vitamin D 3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice

AU - Kwon, Hyo Jung

AU - Won, Young Suk

AU - Nam, KiTaek

AU - Yoon, Yeo Dae

AU - Jee, Hyang

AU - Yoon, Won Kee

AU - Nam, Ki Hoan

AU - Kang, Jong Soon

AU - Han, Sang Uk

AU - Choi, In Pyo

AU - Kim, Dae Yong

AU - Kim, Hyoung Chin

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Objective: Vitamin D 3 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 noncancerous 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-βB 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 pyloriassociated tumourigenesis.

AB - Objective: Vitamin D 3 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 noncancerous 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-βB 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 pyloriassociated tumourigenesis.

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