Lack of nuclear expression of hairy and enhancer of split-1 (HES1) in pancreatic endocrine tumors.
The Notch signaling cascade plays a vital role in the proliferation and differentiation of cells during pancreatic development. Cell line experiments have suggested the involvement of Notch signaling in pancreatic endocrine tumorigenesis. We investigated the expression of NOTCH1, HES1, HEY1 and ASCL1 in pancreatic endocrine tumors and compared the data to tumor phenotype including hormone production, heredity, and WHO classification. Real-time quantitative PCR and immunohistochemistry were performed on samples of 26 pancreatic endocrine tumors. For comparison, 10 specimens of macroscopically normal pancreas were analyzed using immunohistochemistry. The subcellular localization of proteins was determined. Neither hormone production, nor heredity, or WHO classification was found to be associated with the expression of these proteins. There were discrepancies between mRNA and protein expression levels. All tumors displayed ASCL1 immunoreactivity. HES1 immunoreactivity was lacking altogether in 46% of the tumors, and in the remaining lesions its expression was weak and confined to the cytoplasm. In the nontumorous pancreatic endocrine cells, weak nuclear expression of HES1 as well as of HEY1 and NOTCH1 was observed. There was a significant positive correlation between NOTCH1 and HES1 mRNA levels, but no indication that HES1 was inhibiting ASCL1 transcription was found. No nuclear expression of HES1 was found in the tumors. This lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas.
Johansson
T
T
Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
Lejonklou
M H
MH
Ekeblad
S
S
Stålberg
P
P
Skogseid
B
B
D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C065500:ASCL1 protein, human; C485631:HEY1 protein, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human