scholarly journals THBS4/Integrin α2 axis mediates BM-MSCs promote angiogenesis of gastric cancer associated with chronic Helicobacter pylori infection

2021 ◽  
Author(s):  
LingNan He ◽  
WeiJun Wang ◽  
HuiYing Shi ◽  
Chen Jiang ◽  
HaiLing Yao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Endothelial Cells ◽  
Helicobacter Pylori ◽  
Umbilical Vein ◽  
Mucosal Injury ◽  
Akt Pathway ◽  
Human Gastric Cancer ◽  
H Pylori ◽  
Integrin Α2

Abstract BackgroundBM-MSCs contribute to Helicobacter pylori (H. pylori)-induced gastric cancer, but its mechanism is still unclear. The aim of our study is to investigate the specific role and mechanism of BM-MSCs in H. pylori-induced gastric cancer.Main methodsMice were received total bone marrow transplantations and then infected with H. pylori. BM-MSCs were extracted and transplanted to gastric serosal layer of mice infected with H. pylori chronically. Hematoxylin and eosin staining, immunohistochemistry staining and immunofluorescence were performed to detect the tumor growth and angiogenesis in mice stomach tissues. Chicken chorioallantoic membrane assay, xenograft tumor model, and Human umbilical vein endothelial cells tube formation assay were used for in vivo and in vitro angiogenesis study. THBS4 was screened out from RNA-SEQ Analysis with gastric tissues of BM-MSCs transplantation into H. pylori infected mice.ResultsBM-MSCs can migrate to the site of chronic mucosal injury and promote tumor angiogenesis associated with chronic H. pylori infection. Migration of BM-MSCs to the site of chronic mucosal injury induced the up-regulation of THBS4, which was evident also in human gastric cancer, and correlated with more blood vessel formation and worse outcome. THBS4/Integrin α2 axis exhibited promoting angiogenesis by facilitating PI3K/AKT pathway in endothelial cells.ConclusionsOur results discover that BM-MSCs have a new pro-angiogenic effect in chronic H. pylori infection microenvironment, primarily through THBS4/Integrin α2 axis, which activated PI3K/AKT pathway in endothelial cells and eventually induced formation of new tumor vessels.

scholarly journals Role of TNF-α-Inducing Protein Secreted by Helicobacter pylori as a Tumor Promoter in Gastric Cancer and Emerging Preventive Strategies

Toxins ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 181
Author(s):  
Masami Suganuma ◽  
Tatsuro Watanabe ◽  
Eisaburo Sueoka ◽  
In Kyoung Lim ◽  
Hirota Fujiki
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Cell Surface Receptor ◽  
Tumor Promoter ◽  
Cancer Development ◽  
Human Gastric Cancer ◽  
Tnf Α ◽  
Surface Receptor ◽  
H Pylori ◽  
Factor Α

The tumor necrosis factor-α (TNF-α)-inducing protein (tipα) gene family, comprising Helicobacter pylori membrane protein 1 (hp-mp1) and tipα, has been identified as a tumor promoter, contributing to H. pylori carcinogenicity. Tipα is a unique H. pylori protein with no similarity to other pathogenicity factors, CagA, VacA, and urease. American H. pylori strains cause human gastric cancer, whereas African strains cause gastritis. The presence of Tipα in American and Euro-Asian strains suggests its involvement in human gastric cancer development. Tipα secreted from H. pylori stimulates gastric cancer development by inducing TNF-α, an endogenous tumor promoter, through its interaction with nucleolin, a Tipα receptor. This review covers the following topics: tumor-promoting activity of the Tipα family members HP-MP1 and Tipα, the mechanism underlying this activity of Tipα via binding to the cell-surface receptor, nucleolin, the crystal structure of rdel-Tipα and N-terminal truncated rTipα, inhibition of Tipα-associated gastric carcinogenesis by tumor suppressor B-cell translocation gene 2 (BTG2/TIS21), and new strategies to prevent and treat gastric cancer. Thus, Tipα contributes to the carcinogenicity of H. pylori by a mechanism that differs from those of CagA and VacA.

scholarly journals In VitroInhibition ofHelicobacter pyloriGrowth by Redox Cycling Phenylaminojuglones

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Julio Benites ◽  
Héctor Toledo ◽  
Felipe Salas ◽  
Angélica Guerrero ◽  
David Rios ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Antibacterial Activity ◽  
Active Compound ◽  
Metabolic Pathways ◽  
Growth Inhibitor ◽  
Growth Inhibitors ◽  
Design Synthesis ◽  
H Pylori

Infection byHelicobacter pyloriincreases 10 times the risk of developing gastric cancer. Juglone, a natural occurring 1,4-naphthoquinone, preventsH. pylorigrowth by interfering with some of its critical metabolic pathways. Here, we report the design, synthesis, andin vitroevaluation of a series of juglone derivatives, namely, 2/3-phenylaminojuglones, as potentialH. pylorigrowth inhibitors. Results show that 5 out of 12 phenylaminojuglones (at 1.5 μg/mL) were 1.5–2.2-fold more active than juglone. Interestingly, most of the phenylaminojuglones (10 out of 12) were 1.1–2.8 fold more active than metronidazole, a knownH. pylorigrowth inhibitor. The most active compound, namely, 2-((3,4,5-trimethoxyphenyl)amino)-5-hydroxynaphthalene-1,4-dione 7, showed significant higher halo of growth inhibitions (HGI = 32.25 mm) to that of juglone and metronidazole (HGI = 14.50 and 11.67 mm). Structural activity relationships of the series suggest that the nature and location of the nitrogen substituents in the juglone scaffold, likely due in part to their redox potential, may influence the antibacterial activity of the series.

scholarly journals Transcriptome Analysis of the Inhibitory Effect of Astaxanthin on Helicobacter pylori-Induced Gastric Carcinoma Cell Motility

Marine Drugs ◽  
2020 ◽  
Vol 18 (7) ◽  
pp. 365 ◽  
Author(s):  
Suhn Hyung Kim ◽  
Hyeyoung Kim
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Gastric Carcinoma ◽  
Cell Motility ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Pcr Analysis ◽  
Human Gastric Cancer ◽  
Gastric Carcinoma Cell ◽  
H Pylori

Helicobacter pylori (H. pylori) infection promotes the metastasis of gastric carcinoma cells by modulating signal transduction pathways that regulate cell proliferation, motility, and invasion. Astaxanthin (ASTX), a xanthophyll carotenoid, is known to inhibit cancer cell migration and invasion, however the mechanism of action of ASTX in H. pylori-infected gastric epithelial cells is not well understood. To gain insight into this process, we carried out a comparative RNA sequencing (RNA-Seq) analysis of human gastric cancer AGS (adenocarcinoma gastric) cells as a function of H. pylori infection and ASTX administration. The results were used to identify genes that are differently expressed in response to H. pylori and ASTX. Gene ontology (GO) analysis identified differentially expressed genes (DEGs) to be associated with cell cytoskeleton remodeling, motility, and/or migration. Among the 20 genes identified, those encoding c-MET, PI3KC2, PLCγ1, Cdc42, and ROCK1 were selected for verification by real-time PCR analysis. The verified genes were mapped, using signaling networks contained in the KEGG database, to create a signaling pathway through which ASTX might mitigate the effects of H. pylori-infection. We propose that H. pylori-induced upregulation of the upstream regulator c-MET, and hence, its downstream targets Cdc42 and ROCK1, is suppressed by ASTX. ASTX is also suggested to counteract H. pylori-induced activation of PI3K and PLCγ. In conclusion, ASTX can suppress H. pylori-induced gastric cancer progression by inhibiting cytoskeleton reorganization and reducing cell motility through downregulation of c-MET, EGFR, PI3KC2, PLCγ1, Cdc42, and ROCK1.

In vitro sensitivity of human gastric cancer cells (HGC‐27) to Helicobacter pylori cytotoxin

2003 ◽  
Vol 38 (12) ◽  
pp. 1228-1234 ◽  
Author(s):  
A. Pessina ◽  
M. Bayo ◽  
C. Croera ◽  
F. Meringolo ◽  
M. G. Neri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Cancer Cells ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
In Vitro Sensitivity

scholarly journals Discovery and Validation of Novel Methylation Markers in Helicobacter pylori-Associated Gastric Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Huan Wang ◽  
Nian-Shuang Li ◽  
Cong He ◽  
Chuan Xie ◽  
Yin Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Dna Methylation ◽  
Helicobacter Pylori ◽  
Gene Expression Data ◽  
Functional Enrichment ◽  
Expression Data ◽  
H Pylori

Previous studies have shown that abnormal methylation is an early key event in the pathogenesis of most human cancers, contributing to the development of tumors. However, little attention has been given to the potential of DNA methylation patterns as markers for Helicobacter pylori- (H. pylori-) associated gastric cancer (GC). In this study, an integrated analysis of DNA methylation and gene expression was conducted to identify some potential key epigenetic markers in H. pylori-associated GC. DNA methylation data of 28 H. pylori-positive and 168 H. pylori-negative GC samples were compared and analyzed. We also analyzed the gene expression data of 18 H. pylori-positive and 145 H. pylori-negative GC cases. Finally, the results were verified by in vitro and in vivo experiments. A total of 5609 differentially methylated regions associated with 2454 differentially methylated genes were identified. A total of 228 differentially expressed genes were identified from the gene expression data of H. pylori-positive and H. pylori-negative GC cases. The screened genes were analyzed for functional enrichment. Subsequently, we obtained 28 genes regulated by methylation through a Venn diagram, and we identified five genes (GSTO2, HUS1, INTS1, TMEM184A, and TMEM190) downregulated by hypermethylation. HUS1, GSTO2, and TMEM190 were expressed at lower levels in GC than in adjacent samples ( P < 0.05 ). Moreover, H. pylori infection decreased HUS1, GSTO2, and TMEM190 expression in vitro and in vivo. Our study identified HUS1, GSTO2, and TMEM190 as novel methylation markers for H. pylori-associated GC.

scholarly journals Helicobacter pylori Colonization Drives Urokinase Receptor (uPAR) Expression in Murine Gastric Epithelium During Early Pathogenesis

2020 ◽  
Vol 8 (7) ◽  
pp. 1019
Author(s):  
Warner Alpízar-Alpízar ◽  
Mette E. Skindersoe ◽  
Lone Rasmussen ◽  
Mette C. Kriegbaum ◽  
Ib J. Christensen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Protein Expression ◽  
De Novo ◽  
Urokinase Receptor ◽  
Gastric Epithelium ◽  
Upar Expression ◽  
H Pylori

(1) Background: Persistent Helicobacter pylori infection is the most important risk factor for gastric cancer. The urokinase receptor (uPAR) is upregulated in lesions harboring cancer invasion and inflammation. Circumstantial evidence tends to correlate H. pylori colonization with increased uPAR expression in the human gastric epithelium, but a direct causative link has not yet been established in vivo; (2) Methods: In a mouse model of H. pylori-induced gastritis, we investigated the temporal emergence of uPAR protein expression in the gastric mucosa in response to H. pylori (SS1 strain) infection; (3) Results: We observed intense uPAR immunoreactivity in foveolar epithelial cells of the gastric corpus due to de novo synthesis, compared to non-infected animals. This uPAR induction represents a very early response, but it increases progressively over time as do infiltrating immune cells. Eradication of H. pylori infection by antimicrobial therapy causes a regression of uPAR expression to its physiological baseline levels. Suppression of the inflammatory response by prostaglandin E2 treatment attenuates uPAR expression. Notwithstanding this relationship, H. pylori does induce uPAR expression in vitro in co-cultures with gastric cancer cell lines; (4) Conclusions: We showed that persistent H. pylori colonization is a necessary event for the emergence of a relatively high uPAR protein expression in murine gastric epithelial cells.

scholarly journals Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments

Gut ◽  
2017 ◽  
Vol 67 (10) ◽  
pp. 1793-1804 ◽  
Author(s):  
Jennifer M Noto ◽  
Abha Chopra ◽  
John T Loh ◽  
Judith Romero-Gallo ◽  
M Blanca Piazuelo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Genetic Variation ◽  
Prolonged Exposure ◽  
Dietary Factors ◽  
High Salt ◽  
Premalignant Lesions ◽  
H Pylori

ObjectiveHelicobacter pylori is the strongest risk factor for gastric cancer; however, the majority of infected individuals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of H. pylori to in vivo carcinogenic microenvironments results in genetic modification important for disease.DesignWhole genome sequencing of genetically related H. pylori strains that differ in virulence and targeted H. pylori sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed.ResultsA total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference H. pylori genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within fur (FurR88H). To investigate the direct role of low iron and/or high salt, H. pylori was continuously cultured in vitro under low iron or high salt conditions to assess fur genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, fur was sequenced in 339 clinical H. pylori strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034).ConclusionThese results indicate that specific genetic variation arises within H. pylori strains during in vivo adaptation to conditions conducive for gastric carcinogenesis.

scholarly journals Functional Analysis of the cag Pathogenicity Island in Helicobacter pylori Isolates from Patients with Gastritis, Peptic Ulcer, and Gastric Cancer

2004 ◽  
Vol 72 (2) ◽  
pp. 1043-1056 ◽  
Author(s):  
Steffen Backert ◽  
Tobias Schwarz ◽  
Stephan Miehlke ◽  
Christian Kirsch ◽  
Christian Sommer ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Peptic Ulcer ◽  
Pathogenicity Island ◽  
Epidemiological Studies ◽  
Disease Development ◽  
Gastric Diseases ◽  
H Pylori ◽  
Gastric Cancer Patients

ABSTRACT Helicobacter pylori is the causative agent of a variety of gastric diseases, but the clinical relevance of bacterial virulence factors is still controversial. Virulent strains carrying the cag pathogenicity island (cagPAI) are thought to be key players in disease development. Here, we have compared cagPAI-dependent in vitro responses in H. pylori isolates obtained from 75 patients with gastritis, peptic ulcer, and gastric cancer (n = 25 in each group). AGS gastric epithelial cells were infected with each strain and assayed for (i) CagA expression, (ii) translocation and tyrosine phosphorylation of CagA, (iii) c-Src inactivation, (iv) cortactin dephosphorylation, (v) induction of actin cytoskeletal rearrangements associated with cell elongation, (vi) induction of cellular motility, and (vii) secretion of interleukin-8. Interestingly, we found high but similar prevalences of all of these cagPAI-dependent host cell responses (ranging from 56 to 80%) among the various groups of patients. This study revealed CagA proteins with unique features, CagA subspecies of various sizes, and new functional properties for the phenotypic outcomes. We further showed that induction of AGS cell motility and elongation are two independent processes. Our data corroborate epidemiological studies, which indicate a significant association of cagPAI presence and functionality with histopathological findings in gastritis, peptic ulcer, and gastric cancer patients, thus emphasizing the importance of the cagPAI for the pathogenicity of H. pylori. Nevertheless, we found no significant association of the specific H. pylori-induced responses with any particular patient group. This may indicate that the determination of disease development is highly complex and involves multiple bacterial and/or host factors.

scholarly journals Inhibition of Helicobacter pylori and Gastric Cancer Cells by Lipid Aldehydes from Viburnum opulus (Adoxaceae)

2007 ◽  
Vol 2 (10) ◽  
pp. 1934578X0700201
Author(s):  
Maria Teresa Laux ◽  
Manuel Aregullin ◽  
Eloy Rodriguez
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Gastric Cancer Cell Line ◽  
Cancer Cell Line ◽  
Peptic Ulcers ◽  
Viburnum Opulus ◽  
Gastric Cancer Cells ◽  
H Pylori ◽  
Lipid Aldehydes

A unique group of bioactive, naturally occurring lipid aldehydes were isolated from the fruits of Viburnum opulus, (family Adoxaceae). The natural occurrences of these fatty acid derived aldehydes are reported here for the first time. Helicobacter pylori is a prevalent gastroduodenal pathogen, a causal agent of chronic gastritis and peptic ulcers and an important co-factor in gastric cancer development. We investigated the chemistry and bioactivity of these active constituents by evaluating their ability to inhibit the growth of H. pylori and to induce apoptosis in a gastric cancer cell line (CRL-5971) in vitro.

scholarly journals Helicobacter pylori Infection-Induced Hepatoma-Derived Growth Factor Regulates the Differentiation of Human Mesenchymal Stem Cells to Myofibroblast-Like Cells

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 479 ◽  
Author(s):  
Chung-Jung Liu ◽  
Yao-Kuang Wang ◽  
Fu-Chen Kuo ◽  
Wen-Hung Hsu ◽  
Fang-Jung Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Helicobacter Pylori ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Tumor Cell ◽  
Critical Role ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
H Pylori

Hepatoma-derived growth factor (HDGF) plays a critical role in tumor cell proliferation, anti-apoptosis, VEGF expression, lymph node metastasis and poor prognosis in human gastric cancer. Gastric cancer, as one of the most prevalent cancers worldwide, is the second leading cause of cancer-related mortality in the world for the prognosis of gastric cancer is generally poor, especially in patients with advanced stage. Helicobacter pylori (H. pylori) infection causes the chronic inflammation of stomach as well as the development of gastric cancer, with a three to six-fold increased risk of gastric cancer. Carcinoma-associated fibroblasts (CAFs) are myofibroblasts in tumor microenvironment, which possess various abilities to promote the progression of cancer by stimulating neoangiogenesis, proliferation, migration, invasion and therapy resistance of tumor cell. Mesenchymal stem cells (MSCs) are reported to promote tumor malignance through differentiation of MSCs toward CAFs. In the present study, we demonstrated that H. pylori infection promotes HDGF expression in human gastric cancer cells. HBMMSCs treated with HDGF assume properties of CAF-like myofibroblastic phenotypes, including expression of myofibroblast markers (α-smooth muscle actin (α-SMA), procollagen α1, tropomyoson I, desmin, fibroblast activation protein (FAP)), and fibroblast markers (prolyl-4-hydroxylase A1 (PHA1) and fibroblast specific protein-1 (FSP-1)/S100A4). HDGF recruits HBMMSCs, and then HBMMSCs further contributes to cell survival and invasive motility in human gastric cancer cells. Treatment of HDGF neutralizing antibody (HDGF-NAb) and serum significantly inhibit HDGF-regulated differentiation and recruitment of HBMMSCs. These findings suggest that HDGF might play a critical role in gastric cancer progress through stimulation of HBMMSCs differentiation to myofibroblast-like cells.

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