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Schmidt, Alexej
Publications (7 of 7) Show all publications
Aripaka, K., Gudey, S. K., Zang, G., Schmidt, A., Åhrling, S. S., Österman, L., . . . Landström, M. (2019). TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer. EBioMedicine, 45, 192-207
Open this publication in new window or tab >>TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed) Published
Abstract [en]

Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
beta-Catenin, LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161915 (URN)10.1016/j.ebiom.2019.06.046 (DOI)000475860000026 ()31262711 (PubMedID)2-s2.0-85067957867 (Scopus ID)
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-11-04Bibliographically approved
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2019-05-24Bibliographically approved
Javaheri, A., Kruse, T., Moonens, K., Mejias-Luque, R., Debraekeleer, A., Asche, C. I., . . . Gerhard, M. (2017). Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nature Microbiology, 2(1), Article ID 16189.
Open this publication in new window or tab >>Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs
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2017 (English)In: Nature Microbiology, E-ISSN 2058-5276, Vol. 2, no 1, article id 16189Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here, we identify members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1-mediated signalling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells and enhances the release of pro-inflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a beta-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibody-mediated abrogation of the HopQ function shows. Together, our data suggest the HopQ-CEACAM1 interaction to be a potentially promising novel therapeutic target to combat H. pylori-associated diseases.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Immunology in the medical area Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-133381 (URN)10.1038/nmicrobiol.2016.189 (DOI)000396366300008 ()27748768 (PubMedID)
Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2018-06-09Bibliographically approved
Saberi, S., Schmidt, A., Eybpoosh, S., Esmaili, M., Talebkhan, Y., Mohajerani, N., . . . Mohammadi, M. (2016). Helicobacter pylori Strains from Duodenal Ulcer Patients Exhibit Mixed babA/B Genotypes with Low Levels of BabA Adhesin and Lewis b Binding. Digestive Diseases and Sciences, 61(10), 2868-2877
Open this publication in new window or tab >>Helicobacter pylori Strains from Duodenal Ulcer Patients Exhibit Mixed babA/B Genotypes with Low Levels of BabA Adhesin and Lewis b Binding
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2016 (English)In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 61, no 10, p. 2868-2877Article in journal (Refereed) Published
Abstract [en]

BabA is a Helicobacter pylori cell surface adhesin, which binds to the ABO/Le(b) histo-blood group antigens (Le(b)) and serves as a virulence factor. H. pylori single colonies were isolated from 156 [non-ulcer dyspepsia (NUD) = 97, duodenal ulcer (DU) = 34, gastric cancer (GC) = 25)] patients. babA and babB genes were evaluated by gene/locus-specific PCR. BabA protein expression and Le(b) binding activity were determined by immunoblotting and ELISA, respectively. The combined categorization of H. pylori strains based on high, low or no levels of BabA expression and Le(b) binding, produced 4 groups: (I) BabA-high/Le(b)-high (36 %), (II) BabA-low/Le(b)-low (26 %), (III) BabA-neg/Le(b)-low (30 %) and (IV) BabA-neg/Le(b)-neg (8 %) strains. The majority (63 %) of the BabA-low/Le(b)-low strains exhibited mixed babA/B genotypes as compared to merely 18 % of the BabA-high/Le(b)-high, 15 % of the BabA-neg/Le(b)-neg and 11 % of the BabA-neg/Le(b)-low (P = 0.0001) strains. In contrast to NUD strains, the great majority (70 %) of DU strains were BabA-low/Le(b)-low (11 %, P = 0.0001), which compared to NUD strains, enhanced the risk of DU by 18.8-fold. In parallel, infection with babA/B mixed genotype strains amplified the risk of DU by 3.6-fold (vs. babA-positive: P = 0.01) to 6.9-fold (vs. babA-negative: P = 0.007). Here, we show higher prevalence of mixed babA/B genotypes among BabA-low/Le(b)-low clinical strains. Recombination of babA and babB genes across their loci may yield lower BabA expression and lower Le(b) binding activity. We conclude that H. pylori strains with lower Le(b) binding activity are better adapted for colonization of the gastric metaplastic patches in the duodenum and enhance the risk of duodenal ulcers.

Keywords
Helicobacter pylori, Duodenal ulcer, Mixed babA/B genotypes, BabA, Adhesin
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-127719 (URN)10.1007/s10620-016-4217-z (DOI)000384211900015 ()27318698 (PubMedID)
Available from: 2016-12-21 Created: 2016-11-18 Last updated: 2018-06-09Bibliographically approved
Saberi, S., Schmidt, A., Kurdistani, Z. K., Azari, P., Oghalaie, A., Hosseini, M. E., . . . Mohammadi, M. (2015). BabA Protein Expression and Lewis b Binding is Gene Locus-Dependent. Paper presented at European-Helicobacter-Study-Group 28th International Workshop on Helicobacter and Microbiota in Inflammation and Cancer, SEP 24-26, 2015, Nicosia, CYPRUS. Helicobacter, 20(Suppl. 1), 111-111, Article ID Abstract no.: P05.06.
Open this publication in new window or tab >>BabA Protein Expression and Lewis b Binding is Gene Locus-Dependent
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2015 (English)In: Helicobacter, ISSN 1083-4389, E-ISSN 1523-5378, Vol. 20, no Suppl. 1, p. 111-111, article id Abstract no.: P05.06Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Helicobacter pylori (Hp) adhesion, BabA, is localized on the bacterial cell surface, binds to the fucosylated Lewis b histo-blood group antigen on gastric epithelial cells and is responsible for bacterial colonization in the gastric milieu. The diverse roles of this bacterial adhesion in Hp-induced pathogenesis remain understudied.

Methods: We have isolated single colonies of Hp from 156 (NUD=97, DU=34, GC=25) patients. babA and babB genes were evaluated by gene/locus-specific PCR. BabA protein expression and Lewis b (Leb) binding capacity were determined by immunoblotting and ELISA, respectively.

Results: Leb binding assay identified 36% of the strains as high binders and the remaining 64% with low binding capacity. All (100%) of the strains in the former group expressed BabA protein at high levels (BabA-H). Of the latter group, 40% were BabA low producers (BabA-L) and the remaining 60% produced no detectable BabA protein (BabA-Neg). The majority (73/88, 83%) of the strains expressing BabA protein were babA gene-positive at locus A versus. those at locus B (15/88, 17%, P = 0.034). The same holds true for Lewis b binding. In other words, the former group constitutes larger numbers (44/50, 88%) of Leb high-binders relative to the latter group (6/50, 12%, P = 0.035). Furthermore, amongst the former group, co-presence of babA and babB genes in locus A reduced the probability of Leb binding (P = 0.0001).

Conclusion: Presence of babA gene in locus A is associated with higher BabA protein expression and Lewis b binding. Therefore, gene/locus-specific PCR seems better suited for the assessment of functional BabA protein.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
National Category
Biochemistry and Molecular Biology Biophysics
Identifiers
urn:nbn:se:umu:diva-111506 (URN)000363064400149 ()
Conference
European-Helicobacter-Study-Group 28th International Workshop on Helicobacter and Microbiota in Inflammation and Cancer, SEP 24-26, 2015, Nicosia, CYPRUS
Available from: 2015-12-10 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Fei, Y. Y., Schmidt, A., Bylund, G., Johansson, D. X., Henriksson, S., Lebrilla, C., . . . Zhu, X. D. (2011). Use of real-time, label-free analysis in revealing low-affinity binding to blood group antigens by Helicobacter pylori. Analytical Chemistry, 83(16), 6336-6341
Open this publication in new window or tab >>Use of real-time, label-free analysis in revealing low-affinity binding to blood group antigens by Helicobacter pylori
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2011 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, no 16, p. 6336-6341Article in journal (Refereed) Published
Abstract [en]

Infectious diseases are often initiated by microbial adherence that is mediated by the binding of attachment molecules, termed adhesins, to cell surface receptors on host cells. We present an experimental system, oblique-incidence reflectivity difference (OI-RD) microscopy, which allows the detection of novel, low-affinity microbial attachment mechanisms that may be essential for infectious processes. OI-RD microscopy was used to analyze direct binding of the oncopathogen, Helicobacter pylori ( H. pylori ) to immobilized glycoconjugates in real time with no need for labeling tags. The results suggest the presence of additional Lewis b blood group antigen (Le(b)) binding adhesins that have not been detected previously. OI-RD microscopy also confirmed the high-affinity binding of H. pylori outer-membrane protein BabA to Le(b). The OI-RD microscopy method is broadly applicable to real-time characterization of intact microbial binding to host receptors and offers new strategies to elucidate the molecular interactions of infectious agents with human host cells.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-82538 (URN)10.1021/ac201260c (DOI)000293758800032 ()21721569 (PubMedID)
Funder
Swedish Research Council, 11218Swedish Cancer SocietyNIH (National Institute of Health), R01 AI070803, R01 AI081037, R01 HG003827-04, R01 GM076360-04S1
Available from: 2013-11-05 Created: 2013-11-05 Last updated: 2018-06-08Bibliographically approved
Bugaytsova, J., Chernov, Y. A., Gideonsson, P., Mendez, M., Henriksson, S., Mahdavi, J., . . . Borén, T.Acid Responsive Helicobacter pylori Adherence: Implications for Chronic Infection and Disease.
Open this publication in new window or tab >>Acid Responsive Helicobacter pylori Adherence: Implications for Chronic Infection and Disease
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(English)Manuscript (preprint) (Other academic)
Keywords
Helicobacter pylori
National Category
Microbiology in the medical area
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-120299 (URN)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Available from: 2016-05-14 Created: 2016-05-14 Last updated: 2018-06-07
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