TY - JOUR
T1 - TNF-/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells
AU - Oshima, H.
AU - Ishikawa, T.
AU - Yoshida, G. J.
AU - Naoi, K.
AU - Maeda, Y.
AU - Naka, K.
AU - Ju, X.
AU - Yamada, Y.
AU - Minamoto, T.
AU - Mukaida, N.
AU - Saya, H.
AU - Oshima, M.
N1 - Funding Information:
We thank Manami Watanabe and Ayako Tsuda for their excellent technical assistance. This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas (no. 22114005) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and CREST, the Japan Science and Technology Agency, Japan.
PY - 2014/7/17
Y1 - 2014/7/17
N2 - 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.
AB - 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.
KW - TNF-A
KW - gastric cancer
KW - inflammation
KW - mouse model
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U2 - 10.1038/onc.2013.356
DO - 10.1038/onc.2013.356
M3 - Article
C2 - 23975421
AN - SCOPUS:84904628057
SN - 0950-9232
VL - 33
SP - 3820
EP - 3829
JO - Oncogene
JF - Oncogene
IS - 29
ER -
