Epithelial- mesenchymal transition in human gastric cancer cell lines induced by TNF- a- inducing protein of Helicobacter pylori

Helicobacter pylori strains produce tumor necrosis factor- (TNF-)-inducing protein, Tip as a carcinogenic factor in the gastric epithelium. Tip acts as a homodimer with 38-kDa protein, whereas del-Tip is an inactive monomer. H. pylori isolated from gastric cancer patients secreted large amounts of Tip, which are incorporated into gastric cancer cells by directly binding to nucleolin on the cell surface, which is a receptor of Tip. The binding complex induces expression of TNF- and chemokine genes, and activates NF-B (nuclear factor kappa-light-chain-enhancer of activated B cells). To understand the mechanisms of Tip in tumor progression, we looked at numerous effects of Tip on human gastric cancer cell lines. Induction of cell migration and elongation was found to be mediated through the binding to surface nucleolin, which was inhibited by the nucleolin-targeted siRNAs. Tip induced formation of filopodia in MKN-1 cells, suggesting invasive morphological changes. Tip enhanced the phosphorylation of 11 cancer-related proteins in serine, threonine and tyrosine, indicating activation of MEK-ERK signal cascade. Although the downregulation of E-cadherin was not shown in MKN-1 cells, Tip induced the expression of vimentin, a significant marker of the epithelial-mesenchymal transition (EMT). It is of great importance to note that Tip reduced the Young's modulus of MKN-1 cells determined by atomic force microscopy: This shows lower cell stiffness and increased cell motility. The morphological changes induced in human gastric cancer cells by Tip are significant phenotypes of EMT. This is the first report that Tip is a new inducer of EMT, probably associated with tumor progression in human gastric carcinogenesis. What's new?Helicobacter pylori strains are known to produce TNF- inducing protein (Tip) as a carcinogenic factor in the gastric epithelium. Here the authors sought to understand the underlying mechanisms of tumor progression. They demonstrated that Tip induces migration, elongation, and filopodia of human gastric cancer cell lines. Tip, which decreases cell stiffness, also enhances phosphorylation of cancer-related proteins, and increases the expression of vimentin with activation of MEK-ERK signal cascade. This is the first report that Tip is a new inducer of epithelial-mesenchymal transition, probably associated with tumor progression in human gastric carcinogenesis.