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TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells
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TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells
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Journal Article
TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells
2014
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adaptor Proteins, Vesicular Transport - metabolism
/ Animals
/ Cell Transformation, Neoplastic - genetics
/ Cell Transformation, Neoplastic - immunology
/ Cell Transformation, Neoplastic - metabolism
/ Cellular signal transduction
/ Dendritic Cells - immunology
/ Dendritic Cells - metabolism
/ GTP-Binding Protein alpha Subunits, Gq-G11 - genetics
/ GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
/ Humans
/ Hyaluronan Receptors - metabolism
/ Medicine
/ Mice
/ Neoplastic Stem Cells - immunology
/ Neoplastic Stem Cells - metabolism
/ Oncology
/ Receptors, Tumor Necrosis Factor, Type I - genetics
/ Receptors, Tumor Necrosis Factor, Type I - metabolism
/ Stomach Neoplasms - genetics
/ Stomach Neoplasms - immunology
/ Stomach Neoplasms - metabolism
