RRC ID 44612
Author Oshima H, Ishikawa T, Yoshida GJ, Naoi K, Maeda Y, Naka K, Ju X, Yamada Y, Minamoto T, Mukaida N, Saya H, Oshima M.
Title TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells.
Journal Oncogene
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.
Volume 33(29)
Pages 3820-9
Published 2014-7-17
DOI 10.1038/onc.2013.356
PII onc2013356
PMID 23975421
MeSH 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*
IF 6.854
Times Cited 25
Human and Animal Cells