title: Epithelial-mesenchymal transition in human gastric cancer cell lines induced by TNF-α-inducing protein of Helicobacter pylori.
abstract: 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.
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Kitaadachi-gun, Saitama, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Kaori
authors.initials: K
authors.lastname: Suzuki
authors.forename: Miki
authors.initials: M
authors.lastname: Kurusu-Kanno
authors.forename: Kensei
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Hirota
authors.initials: H
authors.lastname: Fujiki
authors.forename: Masami
authors.initials: M
authors.lastname: Suganuma
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D018625:Microscopy, Atomic Force; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011554:Pseudopodia / Q000187:drug effects; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097796:Nucleolin
chemical_list: D001426:Bacterial Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000097796:Nucleolin; C505332:Tipalpha protein, Helicobacter pylori; C482125:MAP2K1 protein, human
keywords: Tipα; cell motility; filopodia; gastric cancer; nucleolin