New tumor necrosis factor-?-inducing protein released from Helicobacter pylori for gastric cancer progression

Suganuma, Masami; Kurusu, Miki; Suzuki, Kaori; Nishizono, Akira; Murakami, Kazunori; Fujioka, Toshio; Fujiki, Hirota

doi:10.1007/s00432-004-0652-x

Cited by 57 publications

(113 citation statements)

References 31 publications

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“…HP0596 homologues have not been detected in the genomes of related species (Campylobacter jejuni, Helicobacter hepaticus and Wiolinella succinogenes). The product of the hp0596 gene was named TNF-ainducing protein (Tip-a) by Suganuma's group [51].…”

Section: Resultsmentioning

confidence: 99%

“…We showed that Tip-a is involved in stimulation of macrophages as well as in colonization of mouse gastric mucosa. Analysis conducted by others also strongly documented that Tip-a (tumor necrosis factor [TNF] a-inducing protein) is a H. pylori carcinogenic factor involved in chemokine gene induction [28,51]. Although cell fractionation methods indicated localization of Tip-a in the inner membrane, the function of this protein implies surface exposition.…”

Section: Introductionmentioning

confidence: 99%

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Tip-α (hp0596 Gene Product) Is a Highly Immunogenic Helicobacter pylori Protein Involved in Colonization of Mouse Gastric Mucosa

et al. 2008

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A product of the Helicobacter pylori hp0596 gene (Tip-a) is a highly immunogenic homodimeric protein, unique for this bacterium. Cell fractionation experiments indicate that Tip-a is anchored to the inner membrane. In contrast, the three-dimensional model of the protein suggests that Tip-a is soluble or, at least, largely exposed to the solvent. hp0596 gene knockout resulted in a significant decrease in the level of H. pylori colonization as measured by real-time PCR assay. In addition, the Tip-a recombinant protein was determined to stimulate macrophage to produce IL-1a and TNF-a. Both results imply that Tip-a is rather loosely connected to the inner membrane and potentially released during infection.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tip-α (hp0596 Gene Product) Is a Highly Immunogenic Helicobacter pylori Protein Involved in Colonization of Mouse Gastric Mucosa

et al. 2008

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“…4,18,19) Since Tipa is incorporated into the cells not mediated through Type IV secretion system of H. pylori, Tipa is different from CagA or urease. We recently reported the direct interaction of Tipa with nucleolin on the cell surface of MGT-40 cells, although nucleolin is predominantly present in the nucleoli.…”

Section: Discussionmentioning

confidence: 99%

Nucleolin on the Cell Surface as a New Molecular Target for Gastric Cancer Treatment

Watanabe

Hirano

Takahashi

et al. 2010

Biological & Pharmaceutical Bulletin

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Nucleolin is a well-known major non-ribosomal protein consisting of 710 amino acids in nucleolus: biochemically it is a ubiquitous phosphoprotein which serves as regulator of ribosomal biogenesis and maturation, including the control of ribosomal DNA (rDNA) transcription, pre-ribosome packaging, and organization of nucleolar chromatin. 1,2) We recently reported that TNF-a inducing protein (Tipa), a new carcinogenic factor (molecular weight of 19 kDa) which is transcribed from the TNF-a inducing protein (Tipa) gene in the genome of Helicobacter pylori (H. pylori) strain 26695, binds to nucleolin on the cell surface of mouse gastric cancer cell line : This finding provided a new mechanistic insight into gastric cancer development with Tipa mediated through nucleolin.Looking at the unique features of nucleolin in carcinogenesis, it has been reported that the amount of nucleolin is highly elevated in rapidly proliferating cells, such as cancer cell lines, and that nucleolin is a major component of the silver-stained nucleolar organizer region (AgNOR), which is also elevated in cancer cells compared with normal or premalignant cells. 2,6,7) The localization of nucleolin on the cell surface of gastric cancer cell lines attracted our attention because nucleolin had been mainly reported to be present in nucleoli: We discovered that significant amounts of nucleolin are present on the cell surface of gastric cancer cell lines, as determined by cell fractionation method and flow cytometry analysis with anti-nucleolin antibody.Since cell surface nucleolin serves as a receptor for various ligands, including midkine, lactoferrin, endostatin, and human immunodeficiency virus (HIV) particles, it is possible to regulate the cell growth by either a promoting ligand, like midkine, a cytokine regulating cell proliferation and differentiation, or inhibiting ligands, such as lactoferrin and endostatin.8-11) Considering our study of nucleolin on the cell surface, we think that a ligand with anticancer activity can be used to inhibit the growth of gastric cancer cells.The well-investigated anti-cancer aptamer named AS1411 is a DNA aptamer of 26-mer unmodified guanine-rich oligonucleotide; it specifically binds to nucleolin, resulting in inhibitions of nucleolin function and cancer cell growth in vitro and in vivo. 12,13) Since AS1411 is now in Phase II clinical trials as treatment for acute myeloid leukemia and renal cell carcinoma, we think it is worthwhile to study the effects of AS1411 on inhibition of cell growth and cell cycle regulation in gastric cancer cell lines. This manuscript is the first report that the amount of nucleolin is clearly elevated on the cell surface of gastric cancer cell lines, but not in normal mouse glandular stomach, and that AS1411 inhibits growth of gastric cancer cells probably mediated through cell surface nucleolin before it is incorporated into the cells. All the results indicate that nucleolin on the cell surface is a new molecular target for treatment of gastric cancer in humans. Nishihamaboji, Y...

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“…However, a study by Abbas et al (40) conducted on patients with liver cirrhosis observed no statistically significant difference in the levels of TNF-α expression when comparing positive and negative H. pylori groups, or groups with moderate and severe gastropathy (41). TNF-α is a key cytokine in tumor promotion; therefore, it is important to clarify how the pro-inflammatory cytokines induced by H. pylori are involved in the development of gastric cancer (42). Previous studies have demonstrated the presence of the gene encoder of the TNF-α inducer protein (Tipα) in the H. pylori genome, which functions as a carcinogenic factor by inducing the gene expression of TNF-α and activating NF-κB (41,42).…”

Section: Discussionmentioning

confidence: 99%

“…TNF-α is a key cytokine in tumor promotion; therefore, it is important to clarify how the pro-inflammatory cytokines induced by H. pylori are involved in the development of gastric cancer (42). Previous studies have demonstrated the presence of the gene encoder of the TNF-α inducer protein (Tipα) in the H. pylori genome, which functions as a carcinogenic factor by inducing the gene expression of TNF-α and activating NF-κB (41,42).…”

Section: Discussionmentioning

confidence: 99%

Effect of Helicobacter pylori on NFKB1, p38α and TNF-α mRNA expression levels in human gastric mucosa

Oliveira

Biolchi

Medeiros

et al. 2016

Experimental and Therapeutic Medicine

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Abstract.Helicobacter pylori infects ~50% of the world population, causing chronic gastritis and other forms of cellular damage. The present study assessed the influence of H. pylori on the mRNA expression levels of nuclear factor-κB1 (NFKB1), p38α and tumor necrosis factor-α (TNF-α) in human gastric mucosa in a southern Brazilian population. Human gastric tissue was collected by upper endoscopy and H. pylori diagnosis was performed using a rapid urease test and histological analysis. Total RNA was extracted and purified for subsequent cDNA synthesis and analysis by quantitative polymerase chain reaction (qPCR). The gastric tissue samples were divided into four groups as follows: Normal, inactive chronic gastritis, active chronic gastritis and intestinal metaplasia. The SDHA gene was classified as the most stable when compared with ACTB, GAPDH, B2M and HPRT1 genes, and was therefore selected as the reference gene for qPCR data normalization. TNF-α mRNA expression was significantly higher in samples that were positive for H. pylori and with active chronic gastritis. However, no difference was detected in the mRNA expression levels of NFKB1 and p38α between the groups. The present study concluded that the presence of H. pylori is associated with TNF-α upregulation in human gastric mucosa, but had no effect on NFKB1 and p38α mRNA expression levels.

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New tumor necrosis factor-?-inducing protein released from Helicobacter pylori for gastric cancer progression

Abstract: Tipalpha is a new carcinogenic factor released from H. pylori mediated through NF-kappaB activation.

Cited by 57 publications

References 31 publications

Tip-α (hp0596 Gene Product) Is a Highly Immunogenic Helicobacter pylori Protein Involved in Colonization of Mouse Gastric Mucosa

Tip-α (hp0596 Gene Product) Is a Highly Immunogenic Helicobacter pylori Protein Involved in Colonization of Mouse Gastric Mucosa

Nucleolin on the Cell Surface as a New Molecular Target for Gastric Cancer Treatment

Effect of Helicobacter pylori on NFKB1, p38α and TNF-α mRNA expression levels in human gastric mucosa

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