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Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer

The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate, and maintenance of stem cells in several tissues. Aberrant activation of Notch signaling has been described in several tumours and in gastric cancer (GC), activated Notch1 has been associated with de-differentia...

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Autores principales: Piazzi, Giulia, Fini, Lucia, Selgrad, Michael, Garcia, Melissa, Daoud, Yahya, Wex, Thomas, Malfertheiner, Peter, Gasbarrini, Antonio, Romano, Marco, Meyer, Richard L., Genta, Robert M., Fox, James G., Boland, C. Richard, Bazzoli, Franco, Ricciardiello, Luigi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282085/
https://www.ncbi.nlm.nih.gov/pubmed/22249198
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author Piazzi, Giulia
Fini, Lucia
Selgrad, Michael
Garcia, Melissa
Daoud, Yahya
Wex, Thomas
Malfertheiner, Peter
Gasbarrini, Antonio
Romano, Marco
Meyer, Richard L.
Genta, Robert M.
Fox, James G.
Boland, C. Richard
Bazzoli, Franco
Ricciardiello, Luigi
author_facet Piazzi, Giulia
Fini, Lucia
Selgrad, Michael
Garcia, Melissa
Daoud, Yahya
Wex, Thomas
Malfertheiner, Peter
Gasbarrini, Antonio
Romano, Marco
Meyer, Richard L.
Genta, Robert M.
Fox, James G.
Boland, C. Richard
Bazzoli, Franco
Ricciardiello, Luigi
author_sort Piazzi, Giulia
collection PubMed
description The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate, and maintenance of stem cells in several tissues. Aberrant activation of Notch signaling has been described in several tumours and in gastric cancer (GC), activated Notch1 has been associated with de-differentiation of lineage-committed stomach cells into stem progenitors and GC progression. However, the specific role of the Notch1 ligand (DLL1) in GC has not yet been elucidated. To assess the role of DLL1 in GC cancer, the expression of Notch1 and its ligands DLL1 and Jagged1, was analyzed in 8 gastric cancer cell lines (KATOIII, SNU601, SNU719, AGS, SNU16, MKN1, MKN45, TMK1). DLL1 expression was absent in KATOIII, SNU601, SNU719 and AGS. The lack of DLL1 expression in these cells was associated with promoter hypermethylation and 5-aza-2’deoxycitidine caused up-regulation of DLL1. The increase in DLL1 expression was associated with activation of Notch1 signalling, with an increase in cleaved Notch1 intracellular domain (NICD) and Hes1, and down-regulation in Hath1. Concordantly, Notch1 signalling was activated with the overexpression of DLL1. Moreover, Notch1 signalling together with DLL1 methylation were evaluated in samples from 52 GC patients and 21 healthy control as well as in INS-GAS mice infected with H. pylori and randomly treated with eradication therapy. In GC patients, we found a correlation between DLL1 and Hes1 expression, while DLL1 methylation and Hath1 expression were associated with the diffuse and mixed type of gastric cancer. Finally, none of the samples from INS-GAS mice infected with H. pylori, a model of intestinal-type gastric tumorigenesis, showed promoter methylation of DLL1. This study shows that Notch1 activity in gastric cancer is controlled by the epigenetic silencing of the ligand DLL1, and that Notch1 inhibition is associated with the diffuse type of gastric cancer.
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spelling pubmed-32820852012-02-22 Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer Piazzi, Giulia Fini, Lucia Selgrad, Michael Garcia, Melissa Daoud, Yahya Wex, Thomas Malfertheiner, Peter Gasbarrini, Antonio Romano, Marco Meyer, Richard L. Genta, Robert M. Fox, James G. Boland, C. Richard Bazzoli, Franco Ricciardiello, Luigi Oncotarget Research Papers The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate, and maintenance of stem cells in several tissues. Aberrant activation of Notch signaling has been described in several tumours and in gastric cancer (GC), activated Notch1 has been associated with de-differentiation of lineage-committed stomach cells into stem progenitors and GC progression. However, the specific role of the Notch1 ligand (DLL1) in GC has not yet been elucidated. To assess the role of DLL1 in GC cancer, the expression of Notch1 and its ligands DLL1 and Jagged1, was analyzed in 8 gastric cancer cell lines (KATOIII, SNU601, SNU719, AGS, SNU16, MKN1, MKN45, TMK1). DLL1 expression was absent in KATOIII, SNU601, SNU719 and AGS. The lack of DLL1 expression in these cells was associated with promoter hypermethylation and 5-aza-2’deoxycitidine caused up-regulation of DLL1. The increase in DLL1 expression was associated with activation of Notch1 signalling, with an increase in cleaved Notch1 intracellular domain (NICD) and Hes1, and down-regulation in Hath1. Concordantly, Notch1 signalling was activated with the overexpression of DLL1. Moreover, Notch1 signalling together with DLL1 methylation were evaluated in samples from 52 GC patients and 21 healthy control as well as in INS-GAS mice infected with H. pylori and randomly treated with eradication therapy. In GC patients, we found a correlation between DLL1 and Hes1 expression, while DLL1 methylation and Hath1 expression were associated with the diffuse and mixed type of gastric cancer. Finally, none of the samples from INS-GAS mice infected with H. pylori, a model of intestinal-type gastric tumorigenesis, showed promoter methylation of DLL1. This study shows that Notch1 activity in gastric cancer is controlled by the epigenetic silencing of the ligand DLL1, and that Notch1 inhibition is associated with the diffuse type of gastric cancer. Impact Journals LLC 2011-12-31 /pmc/articles/PMC3282085/ /pubmed/22249198 Text en Copyright: © 2011 Piazzi et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
spellingShingle Research Papers
Piazzi, Giulia
Fini, Lucia
Selgrad, Michael
Garcia, Melissa
Daoud, Yahya
Wex, Thomas
Malfertheiner, Peter
Gasbarrini, Antonio
Romano, Marco
Meyer, Richard L.
Genta, Robert M.
Fox, James G.
Boland, C. Richard
Bazzoli, Franco
Ricciardiello, Luigi
Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer
title Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer
title_full Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer
title_fullStr Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer
title_full_unstemmed Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer
title_short Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer
title_sort epigenetic regulation of delta-like1 controls notch1 activation in gastric cancer
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282085/
https://www.ncbi.nlm.nih.gov/pubmed/22249198
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