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In Situ Analysis of Human Menin in Normal and Neoplastic Pancreatic Tissues: Evidence for Differential Expression in Exocrine and Endocrine Cells

Department of Oncology and Surgical Sciences (I.C., D.M.D., T.F., A.R., G.E., L.C.-B., V.C.), University of Padova, I-35128 Padova, Italy; Department of Medical and Surgical Sciences (L.B., C.P., P.F., E.T., F.F.), I-35123 Padova, Italy; Max-Planck Institute of Psychiatry (M.T., U.P.), D-80804 Munich, Germany; and Endocrinology Clinic (M.B.), University of Ancona, 60020 Torrette-Ancona, Italy

Address all correspondence and requests for reprints to: Vincenzo Ciminale, M.D., Dipartimento di Scienze Oncologiche e Chirurgiche, Universita’ di Padova, Via Gattamelata 64, 35128 Padova, Italy. E-mail: v.ciminale{at}unipd.it.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome linked to mutations in the MEN1 gene, which encodes a 610-amino-acid nuclear protein termed menin. Because of the lack of a suitable detection protocol, the in situ expression pattern of menin in human tissues remains to be determined. In this study, we have developed an antimenin monoclonal antibody and an indirect immunofluorescence/laser-scanning microscopy protocol for analyzing menin expression in frozen tissue sections. Because neuroendocrine pancreatic tumors represent a key feature of MEN1, we focused this study on nontumoral pancreas and a small panel of neuroendocrine pancreatic tumors. Results showed that menin was readily detected in nontumoral exocrine cells. In contrast, most islet cells expressing insulin, glucagon, or somatostatin showed considerably weaker levels of menin expression; however, a subpopulation of pancreatic polypeptide-positive cells exhibited a signal comparable with that detected in adjacent exocrine cells. Sporadic endocrine tumors showed variable levels of menin expression, whereas a MEN1-/- gastrinoma scored negative. This report thus provides the first description of the expression pattern of menin in human pancreas in situ and lays the groundwork for further studies of other tissues and tumors.

This work was supported by a startup grant from the University of Padova and by grants from the Ministero dell’Universita’ e della Ricerca Scientifica (MURST no. 990621892/006 and 990621892/007) and the Regione Veneto. D. M. D’Agostino and T. Ferro were supported by fellowships from the Fondazione Italiana per la Ricerca sul Cancro and Istituto Superiore di Sanita’, respectively.

I.C., D.M.D., and T.F. contributed equally to the work.

Abbreviations: C126men, Portion of MEN1 coding for the C-terminal 126 amino acids of menin; GST, glutathione-S-transferase; IF/LSM, immunofluorescence/laser-scanning microscopy; MEN1, multiple endocrine neoplasia type 1; NSE, neuron-specific enolase; PP, pancreatic polypeptide.

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