TNF-/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells

H. Oshima, T. Ishikawa, G. J. Yoshida, K. Naoi, Y. Maeda, K. Naka, X. Ju, Y. Yamada, T. Minamoto, N. Mukaida, Hideyuki Saya, M. Oshima

Research output: Contribution to journalArticle

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Abstract

Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-) is a proinflammatory cytokine, and polymorphism in the TNF- gene increases the risk of gastric cancer. We herein investigated the role of TNF- in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF- (Tnf) or TNF- receptor TNFR1 (Tnfrsf1a) knockout mice to generate Tnf-/-Gan and Tnfrsf1a-/-Gan mice, respectively, and examined their tumor phenotypes. Notably, both Tnf-/-Gan mice and Tnfrsf1a-/-Gan mice showed similar, significant suppression of gastric tumor growth compared with control Tnf+/+ or Tnfrsf1a+/+ Gan mice. These results indicate that TNF- signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF- expressed by BM-derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion. Moreover, the microarray analysis and colony formation assay indicated that NADPH oxidase organizer 1 (Noxo1) and Gna14 are induced in tumor epithelial cells in a TNF-dependent manner, and have an important role in tumorigenicity and tumor-initiating cell property of gastric cancer cells. Accordingly, it is possible that the activation of TNF-/TNFR1 signaling in the tumor microenvironment promotes gastric tumor development through induction of Noxo1 and Gna14, which contribute to maintaining the tumor cells in an undifferentiated state. The present results indicate that targeting the TNF-/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.

Original languageEnglish
Pages (from-to)3820-3829
Number of pages10
JournalOncogene
Volume33
Issue number29
DOIs
Publication statusPublished - 2014 Jul 17

Fingerprint

Stomach
Carcinogenesis
Tumor Necrosis Factor-alpha
Neoplasms
Stomach Neoplasms
NADPH oxidase 1
Tumor Microenvironment
Neoplastic Stem Cells
Tumor Necrosis Factor Receptors
Helicobacter Infections
Microarray Analysis
Bone Marrow Transplantation
Knockout Mice
Helicobacter pylori
Bone Marrow Cells
Epithelial Cells
Cytokines
Inflammation
Phenotype
Growth

Keywords

  • gastric cancer
  • inflammation
  • mouse model
  • TNF-A

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Oshima, H., Ishikawa, T., Yoshida, G. J., Naoi, K., Maeda, Y., Naka, K., ... Oshima, M. (2014). TNF-/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells. Oncogene, 33(29), 3820-3829. https://doi.org/10.1038/onc.2013.356

TNF-/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells. / Oshima, H.; Ishikawa, T.; Yoshida, G. J.; Naoi, K.; Maeda, Y.; Naka, K.; Ju, X.; Yamada, Y.; Minamoto, T.; Mukaida, N.; Saya, Hideyuki; Oshima, M.

In: Oncogene, Vol. 33, No. 29, 17.07.2014, p. 3820-3829.

Research output: Contribution to journalArticle

Oshima, H, Ishikawa, T, Yoshida, GJ, Naoi, K, Maeda, Y, Naka, K, Ju, X, Yamada, Y, Minamoto, T, Mukaida, N, Saya, H & Oshima, M 2014, 'TNF-/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells', Oncogene, vol. 33, no. 29, pp. 3820-3829. https://doi.org/10.1038/onc.2013.356
Oshima H, Ishikawa T, Yoshida GJ, Naoi K, Maeda Y, Naka K et al. TNF-/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells. Oncogene. 2014 Jul 17;33(29):3820-3829. https://doi.org/10.1038/onc.2013.356
Oshima, H. ; Ishikawa, T. ; Yoshida, G. J. ; Naoi, K. ; Maeda, Y. ; Naka, K. ; Ju, X. ; Yamada, Y. ; Minamoto, T. ; Mukaida, N. ; Saya, Hideyuki ; Oshima, M. / TNF-/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells. In: Oncogene. 2014 ; Vol. 33, No. 29. pp. 3820-3829.
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