Helicobacter pylori strains 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. pylori isolated 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 of TNF-α and
chemokine genes, 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.