Proteolysis in Helicobacter pylori-Induced Gastric Cancer

Posselt, Gernot; Crabtree, Jean E.; Weßler, Silja

doi:10.3390/toxins9040134

Cited by 29 publications

(22 citation statements)

References 148 publications

(211 reference statements)

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“…In addition, intermediate filament, brain development, proteolysis, negative regulation of endopeptidase activity, keratinocyte differentiation, and peptide cross-linking were predominantly dysfunctional molecular function. As the most significant difference was proteolysis, it is reasonable to infer that Hp actively interferes with host cells by activating cellular proteases and the secretion of bacterial proteases, which has also been reported before 17. As for the pathway, the results suggested that cancer-related pathway 'PI3K-Akt signaling pathway' has the most significant difference.…”

Section: Discussionsupporting

confidence: 59%

Comprehensive Analysis of Aberrantly Expressed ceRNA network in gastric cancer with and without H.pylori infection

Chu¹,

Liu²,

Yuan³

et al. 2019

J. Cancer

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Objective : This study mainly focused on revealing ceRNA network in gastric cancer (GC) with Hp infection after comparing with GC without Hp infection and exploring the biological function and prognostic relevance of related molecules. Methods : The RNA expression profile data of GC patients with or without Hp infection were extracted from TCGA GDC data portal, including 20 GC cases with Hp infection and 168 GC cases without Hp infection. Differentially expressed lncRNAs, miRNAs and mRNAs were unveiled by package edgeR of R, and lncRNA-miRNA-mRNA ceRNA network was constructed by integrating the miRNA target information and the expression data of lncRNAs, miRNAs and mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of aberrantly expressed mRNAs were performed to identify the related biological functions and pathologic pathways, and protein-protein interaction (PPI) network was constructed by STRING database. The overall survival (OS) of aberrantly expression lncRNAs and miRNAs were analyzed by package survival of R. A total of 30 gastric cancer tissues were used to validate the bioinformatics analysis results by real-time PCR. Results : Among the 32 differentially expressed miRNAs, 27 differentially expressed lncRNAs and 257 differentially expressed mRNAs were identified by comparing GC patients with and without Hp infection. Totally 10 miRNA, 11 lncRNA, 219 mRNA were included to build ceRNA network. GO and KEGG analysis revealed that differentially expressed mRNAs involved in the ceRNA network were mainly involved in extracellular exosomes, structural molecular activities, proteolysis and P13K-Akt signaling pathways. And PPI analysis obtained six hub genes of NTS, APOC3, OTX2, KRT13, CALCA, GNG4. Survival analysis showed that four lncRNAs (LINC01254, LINC01287, LINC01524, U95743.1) and four miRNAs (miR-302a, miR-302b, miR-1286, miR-378g) were associated with overall survival of GC with Hp infection. The real-time PCR results showed that, the levels of LINCO1254, LINCO1287, LINCO1524, U95743.1 were significantly higher in Hp positive GC patients than Hp negative patients ( P =0.02, 0.048, 0.04, 0.036, respectively). Conclusion : Using TCGA database for data mining, we have successfully constructed a ceRNA regulatory network of GC with Hp infection, consisting of 10 lncRNAs, 11 miRNAs and 219 mRNAs. These findings might provide critical clues for the regulatory role of ceRNA network in the development of GC with Hp infection.

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Section: Discussionsupporting

confidence: 59%

Comprehensive Analysis of Aberrantly Expressed ceRNA network in gastric cancer with and without H.pylori infection

Chu¹,

Liu²,

Yuan³

et al. 2019

J. Cancer

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“…Hp‐I is related to peptic ulcer disease development. Moreover, long‐standing Hp ‐associated gastritis predisposes to gastric adenocarcinoma and mucosa‐associated lymphoid tissue (MALT) lymphoma development . It is established knowledge nowadays, that microbes and their products are able beyond the local induced inflammation, to orchestrate and shape the character of immune system as well as promote or even inhibit tumorigenesis .…”

Section: Introductionmentioning

confidence: 99%

Review: Impact of Helicobacter pylori on Alzheimer's disease: What do we know so far?

et al. 2017

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“…In many bacterial pathogens, HtrA proteases are widely conserved and play an important role in the virulence and survival of microbes under stress conditions ( Hoy et al, 2013 ; Backert et al, 2017 ; Posselt et al, 2017 ; Skorko-Glonek et al, 2017 ). In addition to the protease function, HtrA acts as a chaperone being responsible for protein quality control and degradation of misfolded proteins in the periplasm ( Kim and Kim, 2005 ; Hoy et al, 2013 ), suggesting that HtrA is highly active under harsh conditions ( Hoy et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Amino-Terminal Processing of Helicobacter pylori Serine Protease HtrA: Role in Oligomerization and Activity Regulation

et al. 2018

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The HtrA family of serine proteases is found in most bacteria, and plays an essential role in the virulence of the gastric pathogen Helicobacter pylori. Secreted H. pylori HtrA (HtrAHp) cleaves various junctional proteins such as E-cadherin disrupting the epithelial barrier, which is crucial for bacterial transmigration across the polarized epithelium. Recent studies indicated the presence of two characteristic HtrAHp forms of 55 and 52 kDa (termed p55 and p52, respectively), in worldwide strains. In addition, p55 and p52 were produced by recombinant HtrAHp, indicating auto-cleavage. However, the cleavage sites and their functional importance are yet unclear. Here, we determined the amino-terminal ends of p55 and p52 by Edman sequencing. Two proteolytic cleavage sites were identified (H46/D47 and K50/D51). Remarkably, the cleavage site sequences are conserved in HtrAHp from worldwide isolates, but not in other Gram-negative pathogens, suggesting a highly specific assignment in H. pylori. We analyzed the role of the amino-terminal cleavage sites on activity, secretion and function of HtrAHp. Three-dimensional modeling suggested a trimeric structure and a role of amino-terminal processing in oligomerization and regulation of proteolytic activity of HtrAHp. Furthermore, point and deletion mutants of these processing sites were generated in the recently reported Campylobacter jejuni ΔhtrA/htrAHp genetic complementation system and the minimal sequence requirements for processing were determined. Polarized Caco-2 epithelial cells were infected with these strains and analyzed by immunofluorescence microscopy. The results indicated that HtrAHp processing strongly affected the ability of the protease to disrupt the E-cadherin-based cell-to-cell junctions. Casein zymography confirmed that the amino-terminal region is required for maintaining the proteolytic activity of HtrAHp. Furthermore, we demonstrated that this cleavage influences the secretion of HtrAHp in the extracellular space as an important prerequisite for its virulence activity. Taken together, our data demonstrate that amino-terminal cleavage of HtrAHp is conserved in this pathogen and affects oligomerization and thus, secretion and regulatory activities, suggesting an important role in the pathogenesis of H. pylori.

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Proteolysis in Helicobacter pylori-Induced Gastric Cancer

Cited by 29 publications

References 148 publications

Comprehensive Analysis of Aberrantly Expressed ceRNA network in gastric cancer with and without H.pylori infection

Comprehensive Analysis of Aberrantly Expressed ceRNA network in gastric cancer with and without H.pylori infection

Review: Impact of Helicobacter pylori on Alzheimer's disease: What do we know so far?

Amino-Terminal Processing of Helicobacter pylori Serine Protease HtrA: Role in Oligomerization and Activity Regulation

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