Helicobacter pyloristrains produce tumor necrosis factor-α (TNF-α)-inducing protein, Tipα as a carcinogenic factor in the gastric epithelium. Tipα acts as a homodimer with 38-kDa protein, whereas del-Tipα is an inactive monomer.H. pyloriisolated from gastric cancer patients secreted large amounts of Tipα, which are incorporated into gastric cancer cells by directly binding to nucleolin on the cell surface, which is a receptor of Tipα. The binding complex induces expression ofTNF-α andchemokinegenes, and activates NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). To understand the mechanisms of Tipα in tumor progression, we looked at numerous effects of Tipα 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. Tipα induced formation of filopodia in MKN-1 cells, suggesting invasive morphological changes. Tipα 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, Tipα induced the expression of vimentin, a significant marker of the epithelial–mesenchymal transition (EMT). It is of great importance to note that Tipα 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 Tipα are significant phenotypes of EMT. This is the first report that Tipα is a new inducer of EMT, probably associated with tumor progression in human gastric carcinogenesis.What's new?
Helicobacter pyloristrains are known to produce TNF-α inducing protein (Tipα) as a carcinogenic factor in the gastric epithelium. Here the authors sought to understand the underlying mechanisms of tumor progression. They demonstrated that Tipα induces migration, elongation, and filopodia of human gastric cancer cell lines. Tipα, 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 Tipα is a new inducer of epithelial-mesenchymal transition, probably associated with tumor progression in human gastric carcinogenesis.