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

Oncogene. 2014 Jul 17;33(29):3820-9. doi: 10.1038/onc.2013.356. Epub 2013 Aug 26.

Abstract

Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-α) is a proinflammatory cytokine, and polymorphism in the TNF-α gene increases the risk of gastric cancer. We herein investigated the role of TNF-α in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF-α (Tnf) or TNF-α 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-α signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF-α 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-α-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-α/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-α/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Humans
  • Hyaluronan Receptors / metabolism
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Hyaluronan Receptors
  • NOXO1 protein, human
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • GNA14 protein, human
  • GTP-Binding Protein alpha Subunits, Gq-G11