Significance of Notch1 Signaling Pathway in Human Pancreatic Development and Carcinogenesis

摘要

In animal studies, Notch1 signaling pathway plays an important role in the pancreatic embryogenesis by promoting pancreatic progenitor cell self-renewal and exocrine linage development. The persistent activation of Notch pathway could arrest the organ development and keep cells at an undifferentiated stage. Studies have shown that Notch1 signaling pathway is up-regulated in invasive pancreatic ductal adenocarcinoma (PDAC). Here we examined the expression pattern of Notch1 and Hes1 in human fetal pancreas tissues to elucidate the role of Notch1 in human pancreatic embryonic development. We also compared Notch1 expression in tissues from PDAC, chronic pancreatitis and pancreatic intraepithelial neoplasia (PanIN). Our data show that Notch1/Hes1 signaling pathway is activated during early pancreatic embryogenesis and reaches the highest at birth. After pancreas is fully developed, Notch1/Hes1 pathway is inactivated even though Notch1 protein cell-surface expression is up-regulated. We also showed that the expression of both Notch1 and Hes1 are present in 50% (33/66) of PDACs, but not in PanINs. These findings indicate that Notch1 activation is only apparent in late stage of pancreatic carcinogenesis, suggesting that treatment with Notch signaling inhibitors including γ-secretase should be selectively used for PDACs with confirmed Notch1 signaling activation.