Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells.
OBJECTIVE
To investigate if transcription factors involved in pancreatic differentiation and regeneration are present in pancreatic endocrine tumors and if they are differentially expressed in normal pancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreas.


METHODS
The expression of neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POU class 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomal protein L10 (RPL10), delta-like 1 homolog (Drosophila; DLK1), and menin was analyzed by immunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patients with MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens from Men1 heterozygous and wild type mice. Quantitative polymerase chain reaction was performed in a subset of human tumors.


RESULTS
Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factors were significantly more expressed in the cytoplasm of Men1 heterozygous mouse islet cells compared with wild type islets; the latter showed an exclusively nuclear reactivity. The degree of Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets of heterozygous and wild type mice. The expressions of RPL10 and NEUROD1 were prominent in the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas had significantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types.


CONCLUSIONS
Transcription factors involved in pancreatic development show altered expression and subcellular localization in MEN1 nontumorous pancreas and pancreatic endocrine tumors.
Lejonklou
Margareta H
MH
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Edfeldt
Katarina
K
Johansson
Térèse A
TA
Stålberg
Peter
P
Skogseid
Britt
B
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050809:POU Domain Factors / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D000080882:Ribosomal Protein L10; D012269:Ribosomal Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D012269:Ribosomal Proteins; D015534:Trans-Activators; C512941:DLK1 protein, human; C512925:Dlk1 protein, mouse; C093970:NEUROD1 protein, human; C498695:NEUROG3 protein, human; C501008:Neurod1 protein, mouse; C407737:Neurog3 protein, mouse; C091774:POU3F4 protein, human; C000630686:RPL10 protein, human; C000630690:Rpl10 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C074067:Pou3f4 protein, mouse