Background: Apart from inactivation of the MEN1 gene, molecular events essential for tumorigenesis of the endocrine pancreas are poorly characterized. A potentially useful approach for understanding tumor progression is to study transcription factors operating in fetal pancreatic development. The Notch signaling cascade with expression of the transcription factors Hes1, Hey1, and Ascl1 plays a vital role in sustaining the balance between cell proliferation, differentiation and apoptosis during the pancreatic development. They may play a similar role in the development of endocrine pancreatic tumors (EPT).
Aim: To study the expression of Notch1, Hes1, Hey1 and Ascl1 in EPT, by quantitative PCR (qPCR) and Immunohistochemistry (IHC)
Material and methods: Notch1, Hes1, Hey1, and Ascl1 mRNA and protein expression were investigated in 26 EPT (ten were MEN1 associated). Immunohistochemistry was also performed on 11 normal pancreatic tissues adjacent to the tumor (five MEN1 and six sporadic). The immunoreactivity was graded (negative, weak, moderate or strong), and sublocalization of expression as nuclear and/or cytoplasmatic was determined.
Results: The statistical analysis of the qPCR data revealed a correlation between the Notch1-Hes1 expressions in EPT. All tumors displayed Ascl1 immunoreactivity, which was graded as strong in 85%. Hes1 expression in EPT was graded as invariably weak, or completely absent (30%). In normal islets a weak nuclear Hes1 staining was observed. Hey1 and Notch1 were expressed in the cytoplasm and nucleus of tumor cells and normal endocrine tissue.
Conclusions: Ascl1 is invariably and abundantly expressed in EPT. Hes1 is either lacking or weakly expressed and confined to the cytoplasm of EPT. The lack of Hes1 in tumor cell nuclei could contribute to the prominent Ascl1 expression in EPT. These results show that Notch1, Hes1, Hey1 and Ascl1 are variable expressed in EPT and normal pancreatic tissues; and that they may be involved in endocrine