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.
Highlights
There is an overall worldwide decline in incidence, gastric cancer (GC) is still the fourth more common cancer and the second leading cause of cancerrelated deaths [1]
In order to evaluate a possible role of the Notch system in gastric carcinogenesis, we screened a panel of 8 GC cell lines for the expression of Notch1 and its ligands DLL1 and Jagged1 at the RNA level by RT-PCR
We found that Notch1 and Jagged1 were expressed in the entire panel, while DLL1 varied quantitatively with the cell lines and was absent in KATOIII, SNU601, SNU719 and AGS (Figure 1A)
Summary
There is an overall worldwide decline in incidence, gastric cancer (GC) is still the fourth more common cancer and the second leading cause of cancerrelated deaths [1]. The best-characterized Notch effectors are the bHLH protein Hairy/Enhancer of Split (HES), which suppress the expression of downstream genes such as Neurogenin and Hath. The best-characterized Notch effectors are the bHLH protein Hairy/Enhancer of Split (HES), which suppress the expression of downstream genes such as Neurogenin and Hath1 These genes play a critical role in cell lineage commitment and drive cell fates and differentiation in several tissues [89]. Notch activity is involved in the inhibition of chief cell differentiation and Hath over-expression enhances MUC5AC expression in the mucous neck cells of the fundic glands [10, 12]. Notch activation in lineage committed stomach epithelial cells has been shown to induce de-differentiation into stem cells, enhances proliferation and adenomas whereas Notch activation in the antral portion of the stomach does not affect proliferation [13]
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