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Published in: Gastric Cancer 4/2023

Open Access 28-03-2023 | Gastric Cancer | Original Article

The putative pleiotropic functions of meprin β in gastric cancer

Authors: Wiebke Siemsen, Christine Halske, Hans-Michael Behrens, Sandra Krüger, Christoph Becker-Pauly, Christoph Röcken

Published in: Gastric Cancer | Issue 4/2023

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Abstract

Background

The gastric microbiome and inflammation play a key role in gastric cancer (GC) by regulating the immune response in a complex manner and by inflammatory events supporting carcinogenesis. Meprin β is a zinc endopeptidase and participates in tissue homeostasis, intestinal barrier function and immunological processes. It influences local inflammatory processes, dysbiosis and the microbiome. Here, we tested the hypothesis that meprin β is expressed in GC and of tumor biological significance.

Patients and methods

Four hundred forty whole mount tissue sections of patients with therapy-naive GC were stained with an anti-meprin β antibody. The histoscore and staining pattern were analyzed for each case. Following dichotomization at the median histoscore into a “low” and “high” group, the expression was correlated with numerous clinicopathological patient characteristics.

Results

Meprin β was found intracellularly and at the cell membrane of GC. Cytoplasmic expression correlated with the phenotype according to Lauren, microsatellite instability and PD-L1 status. Membranous expression correlated with intestinal phenotype, mucin-1-, E-cadherin-, β-catenin status, mucin typus, microsatellite instability, KRAS mutation and PD-L1-positivity. Patients with cytoplasmic expression of meprin β showed a better overall and tumor-specific survival.

Conclusions

Meprin β is differentially expressed in GC and has potential tumor biological relevance. It might function as a tumor suppressor or promotor depending on histoanatomical site and context.
Literature
1.
go back to reference Camargo MC, Figueiredo C, Machado JC. Review: gastric malignancies: basic aspects. Helicobacter. 2019;24(Suppl 1):e12642.PubMed Camargo MC, Figueiredo C, Machado JC. Review: gastric malignancies: basic aspects. Helicobacter. 2019;24(Suppl 1):e12642.PubMed
3.
go back to reference Robertson, E.S., Microbiome and Cancer. Current Cancer Research, ed. W. El-Deiry. 2019, Gewerbestrasse 11, 6330 Cham, Switzerland. 401 Robertson, E.S., Microbiome and Cancer. Current Cancer Research, ed. W. El-Deiry. 2019, Gewerbestrasse 11, 6330 Cham, Switzerland. 401
5.
go back to reference Ferreira RM, et al. Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut. 2018;67(2):226–36.CrossRefPubMed Ferreira RM, et al. Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut. 2018;67(2):226–36.CrossRefPubMed
6.
go back to reference Wang F, et al. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014;345(2):196–202.CrossRefPubMed Wang F, et al. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014;345(2):196–202.CrossRefPubMed
7.
go back to reference Wroblewski LE, Peek RM Jr. Helicobacter pylori, cancer, and the gastric microbiota. Adv Exp Med Biol. 2016;908:393–408.CrossRefPubMed Wroblewski LE, Peek RM Jr. Helicobacter pylori, cancer, and the gastric microbiota. Adv Exp Med Biol. 2016;908:393–408.CrossRefPubMed
8.
9.
go back to reference Ebrahimi V, et al. Epigenetic modifications in gastric cancer: focus on DNA methylation. Gene. 2020;742: 144577.CrossRefPubMed Ebrahimi V, et al. Epigenetic modifications in gastric cancer: focus on DNA methylation. Gene. 2020;742: 144577.CrossRefPubMed
10.
go back to reference Arnold P, Otte A, Becker-Pauly C. Meprin metalloproteases: Molecular regulation and function in inflammation and fibrosis. Biochim Biophys Acta. 2017;1864(11 Pt B):2096–104.CrossRef Arnold P, Otte A, Becker-Pauly C. Meprin metalloproteases: Molecular regulation and function in inflammation and fibrosis. Biochim Biophys Acta. 2017;1864(11 Pt B):2096–104.CrossRef
11.
go back to reference Jefferson T, et al. The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin beta and ADAM10. Cell Mol Life Sci. 2013;70(2):309–33.CrossRefPubMed Jefferson T, et al. The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin beta and ADAM10. Cell Mol Life Sci. 2013;70(2):309–33.CrossRefPubMed
12.
13.
go back to reference Zhao G, et al. IL-6 mediates the signal pathway of JAK-STAT3-VEGF-C promoting growth, invasion and lymphangiogenesis in gastric cancer. Oncol Rep. 2016;35(3):1787–95.CrossRefPubMed Zhao G, et al. IL-6 mediates the signal pathway of JAK-STAT3-VEGF-C promoting growth, invasion and lymphangiogenesis in gastric cancer. Oncol Rep. 2016;35(3):1787–95.CrossRefPubMed
14.
go back to reference Prox J, Arnold P, Becker-Pauly C. Meprin α and meprin β: Procollagen proteinases in health and disease. Matrix Biol. 2015;44–46:7–13.CrossRefPubMed Prox J, Arnold P, Becker-Pauly C. Meprin α and meprin β: Procollagen proteinases in health and disease. Matrix Biol. 2015;44–46:7–13.CrossRefPubMed
15.
go back to reference Werny L, et al. MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties. FEBS J. 2023;290(1):99–111.CrossRefPubMed Werny L, et al. MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties. FEBS J. 2023;290(1):99–111.CrossRefPubMed
16.
go back to reference Broder C, et al. Metalloproteases meprin alpha and meprin beta are C- and N-procollagen proteinases important for collagen assembly and tensile strength. Proc Natl Acad Sci U S A. 2013;110(35):14219–24.CrossRefPubMedPubMedCentral Broder C, et al. Metalloproteases meprin alpha and meprin beta are C- and N-procollagen proteinases important for collagen assembly and tensile strength. Proc Natl Acad Sci U S A. 2013;110(35):14219–24.CrossRefPubMedPubMedCentral
17.
go back to reference Schutte A, et al. Microbial-induced meprin beta cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc Natl Acad Sci USA. 2014;111(34):12396–401.CrossRefPubMedPubMedCentral Schutte A, et al. Microbial-induced meprin beta cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc Natl Acad Sci USA. 2014;111(34):12396–401.CrossRefPubMedPubMedCentral
18.
go back to reference Jackle F, et al. Metalloprotease meprin beta is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding. Biochem J. 2015;470(1):91–103.CrossRefPubMed Jackle F, et al. Metalloprotease meprin beta is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding. Biochem J. 2015;470(1):91–103.CrossRefPubMed
19.
go back to reference Wichert R, et al. Mucus detachment by host metalloprotease meprin beta requires shedding of its inactive pro-form, which is abrogated by the pathogenic protease RgpB. Cell Rep. 2017;21(8):2090–103.CrossRefPubMed Wichert R, et al. Mucus detachment by host metalloprotease meprin beta requires shedding of its inactive pro-form, which is abrogated by the pathogenic protease RgpB. Cell Rep. 2017;21(8):2090–103.CrossRefPubMed
21.
go back to reference Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.CrossRefPubMed Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.CrossRefPubMed
22.
go back to reference O’Sullivan B, et al. The TNM classification of malignant tumours-towards common understanding and reasonable expectations. Lancet Oncol. 2017;18(7):849–51.CrossRefPubMedPubMedCentral O’Sullivan B, et al. The TNM classification of malignant tumours-towards common understanding and reasonable expectations. Lancet Oncol. 2017;18(7):849–51.CrossRefPubMedPubMedCentral
23.
go back to reference Warneke VS, et al. Prognostic and putative predictive biomarkers of gastric cancer for personalized medicine. Diagn Mol Pathol. 2013;22(3):127–37.CrossRefPubMed Warneke VS, et al. Prognostic and putative predictive biomarkers of gastric cancer for personalized medicine. Diagn Mol Pathol. 2013;22(3):127–37.CrossRefPubMed
24.
25.
go back to reference Mathiak M, et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol. 2017;25:12–24.CrossRefPubMed Mathiak M, et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol. 2017;25:12–24.CrossRefPubMed
26.
go back to reference Warneke VS, et al. Members of the EpCAM signalling pathway are expressed in gastric cancer tissue and are correlated with patient prognosis. Br J Cancer. 2013;109(8):2217–27.CrossRefPubMedPubMedCentral Warneke VS, et al. Members of the EpCAM signalling pathway are expressed in gastric cancer tissue and are correlated with patient prognosis. Br J Cancer. 2013;109(8):2217–27.CrossRefPubMedPubMedCentral
27.
go back to reference Warneke VS, et al. Her2/neu testing in gastric cancer: evaluating the risk of sampling errors. Ann Oncol. 2013;24(3):725–33.CrossRefPubMed Warneke VS, et al. Her2/neu testing in gastric cancer: evaluating the risk of sampling errors. Ann Oncol. 2013;24(3):725–33.CrossRefPubMed
28.
go back to reference Metzger ML, et al. MET in gastric cancer–discarding a 10% cutoff rule. Histopathology. 2016;68(2):241–53.CrossRefPubMed Metzger ML, et al. MET in gastric cancer–discarding a 10% cutoff rule. Histopathology. 2016;68(2):241–53.CrossRefPubMed
29.
go back to reference Böger C, et al. The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: a future perspective for a combined gastric cancer therapy? Oncoimmunology. 2017;6(4): e1293215.CrossRefPubMedPubMedCentral Böger C, et al. The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: a future perspective for a combined gastric cancer therapy? Oncoimmunology. 2017;6(4): e1293215.CrossRefPubMedPubMedCentral
30.
go back to reference Schoop H, et al. Therapy resistance in neoadjuvantly treated gastric cancer and cancer of the gastroesophageal junction is associated with an increased expression of immune checkpoint inhibitors-comparison against a therapy naive cohort. Transl Oncol. 2020;13(2):165–76.CrossRefPubMed Schoop H, et al. Therapy resistance in neoadjuvantly treated gastric cancer and cancer of the gastroesophageal junction is associated with an increased expression of immune checkpoint inhibitors-comparison against a therapy naive cohort. Transl Oncol. 2020;13(2):165–76.CrossRefPubMed
31.
go back to reference Lüllmann-Rauch R. Taschenlehrbuch histologie. New York: Thieme; 2012. p. 629–31. Lüllmann-Rauch R. Taschenlehrbuch histologie. New York: Thieme; 2012. p. 629–31.
32.
go back to reference Simes RJ. An improved Bonferroni procedure for multiple tests of significance. Biometrika. 1986;73(3):751–4.CrossRef Simes RJ. An improved Bonferroni procedure for multiple tests of significance. Biometrika. 1986;73(3):751–4.CrossRef
34.
go back to reference Wang XT, et al. MUC1 immunohistochemical expression as a prognostic factor in gastric cancer: meta-analysis. Dis Mark. 2016;2016:9421571. Wang XT, et al. MUC1 immunohistochemical expression as a prognostic factor in gastric cancer: meta-analysis. Dis Mark. 2016;2016:9421571.
35.
go back to reference Bure IV, Nemtsova MV, Zaletaev DV. Roles of E-cadherin and noncoding RNAs in the epithelial-mesenchymal transition and progression in gastric cancer. Int J Mol Sci. 2019;20(12):2870.CrossRefPubMedPubMedCentral Bure IV, Nemtsova MV, Zaletaev DV. Roles of E-cadherin and noncoding RNAs in the epithelial-mesenchymal transition and progression in gastric cancer. Int J Mol Sci. 2019;20(12):2870.CrossRefPubMedPubMedCentral
37.
go back to reference Katoh M. Multilayered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/betacatenin signaling activation (Review). Int J Mol Med. 2018;42(2):713–25.PubMedPubMedCentral Katoh M. Multilayered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/betacatenin signaling activation (Review). Int J Mol Med. 2018;42(2):713–25.PubMedPubMedCentral
39.
go back to reference Li L, et al. Abnormal β-catenin immunohistochemical expression as a prognostic factor in gastric cancer: a meta-analysis. World J Gastroenterol. 2014;20(34):12313–21. Li L, et al. Abnormal β-catenin immunohistochemical expression as a prognostic factor in gastric cancer: a meta-analysis. World J Gastroenterol. 2014;20(34):12313–21.
40.
go back to reference Cui C, et al. The roles of PD-1/PD-L1 and its signalling pathway in gastrointestinal tract cancers. Clin Exp Pharmacol Physiol. 2019;46(1):3–10.CrossRefPubMed Cui C, et al. The roles of PD-1/PD-L1 and its signalling pathway in gastrointestinal tract cancers. Clin Exp Pharmacol Physiol. 2019;46(1):3–10.CrossRefPubMed
41.
go back to reference Sun L, et al. Gastric cancer mesenchymal stem cells derived IL-8 induces PD-L1 expression in gastric cancer cells via STAT3/mTOR-c-Myc signal axis. Cell Death Dis. 2018;9(9):928.CrossRefPubMedPubMedCentral Sun L, et al. Gastric cancer mesenchymal stem cells derived IL-8 induces PD-L1 expression in gastric cancer cells via STAT3/mTOR-c-Myc signal axis. Cell Death Dis. 2018;9(9):928.CrossRefPubMedPubMedCentral
Metadata
Title
The putative pleiotropic functions of meprin β in gastric cancer
Authors
Wiebke Siemsen
Christine Halske
Hans-Michael Behrens
Sandra Krüger
Christoph Becker-Pauly
Christoph Röcken
Publication date
28-03-2023
Publisher
Springer Nature Singapore
Published in
Gastric Cancer / Issue 4/2023
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-023-01385-2

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