Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer
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1Department of Clinical Medicine, University of Bologna, Bologna, Italy
2Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
3Department of Internal Medicine, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, United States
4Department of Gastroenterology, IRCCS, Istituto Clinico Humanitas, Rozzano, Milan, Italy
5Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
6Institute for Health Care Research and Improvement Baylor Health Care System, Baylor University Medical Center, Dallas, United States
7Internal Medicine and Gastroenterology, Catholic University, Rome, Italy
8Department of Internal Medicine-Gastroenterology, Second University of Naples, Italy
9Department of Pathology, Baylor University Medical Center
10Department of Pathology, VA Medical Center, Dallas, United States
11Division of Comparative Medicine and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Received: December 28, 2011; Accepted: December 31, 2011; Published: December 31, 2011;
Keywords: Gastric cancer, Methylation, Notch, Delta like-1
Dr. Luigi Ricciardiello, email:
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.
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