Helicobacter pylori-secreting protein Tipα is a potent inducer of chemokine gene expressions in stomach cancer cells

Abstract

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-alpha (TNF-alpha) inducing protein (Tipalpha) secreted from H. pylori acts as a tumor promoter in stomach cancer development, and thus started to investigate whether Tipalpha is involved in induction of chemokine genes. Comprehensive gene expression analysis was conducted using DNA microarray and KeyMolnet analyses. The gene expression was quantitatively analyzed by real-time RT-PCR. Comprehensive and quantitative gene expression analyses revealed that Tipalpha induces gene expression of the chemokines Ccl2, Ccl7, Ccl20, Cxcl1, Cxcl2, Cxcl5 and Cxcl10 extensively and simultaneously in mouse stomach cancer cells, MGT-40. Tipalpha induced high levels of chemokine gene expression, whereas inactive deleted Tipalpha, del-Tipalpha, showed only marginal expression, suggesting a correlation between tumor promotion and chemokine gene expression by Tipalpha. MG-132, a proteasome inhibitor which represses NF-kappaB-activation, inhibited chemokine gene expressions. We report here that Tipalpha of H. pylori gene product is a strong inducer of chemokine gene expressions, providing a new model for stomach cancer development.