Abstract
Purpose
Stomach cancer has a high mortality rate in East Asia, and is strongly associated with Helicobacter pylori (H. pylori) infection. H. pylori is known to express chemokine genes in the gastric mucosa, chemokines that are important host immune factors facilitating inflammation and tumor growth. To investigate the mechanism of carcinogenesis in the stomach, it is essential to determine which molecule of H. pylori is involved in induction of chemokines, but this has remained unclear. We previously reported that a tumor necrosis factor-α (TNF-α) inducing protein (Tipα) secreted from H. pylori acts as a tumor promoter in stomach cancer development, and thus started to investigate whether Tipα is involved in induction of chemokine genes.
Methods
Comprehensive gene expression analysis was conducted using DNA microarray and KeyMolnet analyses. The gene expression was quantitatively analyzed by real-time RT-PCR.
Results
Comprehensive and quantitative gene expression analyses revealed that Tipα induces gene expression of the chemokines Ccl2, Ccl7, Ccl20, Cxcl1, Cxcl2, Cxcl5 and Cxcl10 extensively and simultaneously in mouse stomach cancer cells, MGT-40. Tipα induced high levels of chemokine gene expression, whereas inactive deleted Tipα, del-Tipα, showed only marginal expression, suggesting a correlation between tumor promotion and chemokine gene expression by Tipα. MG-132, a proteasome inhibitor which represses NF-κB-activation, inhibited chemokine gene expressions.
Conclusion
We report here that Tipα of H. pylori gene product is a strong inducer of chemokine gene expressions, providing a new model for stomach cancer development.
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Acknowledgments
We thank Drs. Yuichi Kikushima, Hiromi Sato, and Akiko Itai at Institute of Medicinal Molecular Design, Inc. (IMMD) to conduct KeyMolnet analysis of the DNA microarray data. We thank Dr. Masae Tatematsu for his kind gift of MGT-40 cells and Dr. Midori Suenaga for a fruitful discussion. We also thank Kurabo Co. Ltd., Ms. Kinuko Sasada, Ms. Mitsuyo Kato, Ms. Yukari Nagata, Mr. Ryoji Sugiyama, Ms. Jyuri Tateishi and Mr. Tairo Shiraishi for their skillful technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Smoking Research Fund.
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Kuzuhara, T., Suganuma, M., Kurusu, M. et al. Helicobacter pylori-secreting protein Tipα is a potent inducer of chemokine gene expressions in stomach cancer cells. J Cancer Res Clin Oncol 133, 287–296 (2007). https://doi.org/10.1007/s00432-006-0169-6
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DOI: https://doi.org/10.1007/s00432-006-0169-6