Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal adenocarcinoma.
Loss of menin, a tumor suppressor coded by the MEN1 gene, is a key factor in the pathogenesis of multiple endocrine neoplasia type I and in a percentage of sporadic endocrine tumors of the pancreas and parathyroid glands. This study investigated expression of the menin protein in the normal exocrine pancreas and in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumor. Immunofluorescence (IF) analyses showed that menin is expressed at high levels in normal acinar and duct cells. Examination of 24 clinical samples of PDAC revealed a pronounced decrease in menin expression in all tumors examined. To identify alterations underlying this defect, we searched for disruption and epigenetic silencing of the MEN1 gene. Analysis of nine laser-microdissected tumors revealed loss of heterozygosity of intragenic (one tumor) or adjacent (three tumors) MEN1 microsatellite markers. Methylation of CpG sites in the MEN1 promoter was documented in five of 24 tumors. IF analyses also revealed low to undetectable menin expression in the PDAC cell lines MiaPaCa-2 and Panc-1. Ectopic expression of menin in these cells resulted in a marked alteration of the cell cycle, with an increase in the G1/S+G2 ratio. These findings represent the first evidence that the MEN1 gene is a target of mutation and methylation in PDAC and that menin influences the cell cycle profile of duct cells.
Cavallari
Ilaria
I
Department of Oncology and Surgical Sciences, University of Padova, Via Gattamelata 64, Padova 35128, Italy.
Silic-Benussi
Micol
M
Rende
Francesca
F
Martines
Annalisa
A
Fogar
Paola
P
Basso
Daniela
D
Vella
Manuela Della
MD
Pedrazzoli
Sergio
S
Herman
James G
JG
Chieco-Bianchi
Luigi
L
Esposito
Giovanni
G
Ciminale
Vincenzo
V
D'Agostino
Donna M
DM
D000368:Aged; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D046790:Pancreas, Exocrine / Q000166:cytology / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism
C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins