title: Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer.
abstract: 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'dC 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.
authors.affiliation: Department of Clinical Medicine, University of Bologna, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Piazzi
authors.forename: Lucia
authors.initials: L
authors.lastname: Fini
authors.forename: Michael
authors.initials: M
authors.lastname: Selgrad
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.forename: Yahya
authors.initials: Y
authors.lastname: Daoud
authors.forename: Thomas
authors.initials: T
authors.lastname: Wex
authors.forename: Peter
authors.initials: P
authors.lastname: Malfertheiner
authors.forename: Antonio
authors.initials: A
authors.lastname: Gasbarrini
authors.forename: Marco
authors.initials: M
authors.lastname: Romano
authors.forename: Richard L
authors.initials: RL
authors.lastname: Meyer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Genta
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Franco
authors.initials: F
authors.lastname: Bazzoli
authors.forename: Luigi
authors.initials: L
authors.lastname: Ricciardiello
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D001374:Azacitidine; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D000077209:Decitabine; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C500943:Atoh1 protein, mouse; C512925:Dlk1 protein, mouse; C489734:Hes1 protein, mouse; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497762:Notch1 protein, mouse