PMID- 17158767
OWN - NLM
STAT- MEDLINE
DCOM- 20070301
LR  - 20081121
IS  - 1351-0088 (Print)
IS  - 1351-0088 (Linking)
VI  - 13
IP  - 4
DP  - 2006 Dec
TI  - Gene expression profiling in insulinomas of Men1 beta-cell mutant mice reveals 
      early genetic and epigenetic events involved in pancreatic beta-cell 
      tumorigenesis.
PG  - 1223-36
AB  - Mutations of the MEN1 gene lead to the occurrence of multiple endocrine neoplasia 
      type 1 (MEN1). To gain insights into the mechanisms of the tumorigenesis related 
      to MEN1 inactivation, we have used mice in which the Men1 gene was specifically 
      disrupted in pancreatic beta-cells. In these mice, we observed full penetrance of 
      insulinoma with defined histological characteristics of tumorigenesis. To 
      identify the genetic factors taking part in the tumour development, we performed 
      gene expression profiling analysis of these insulinomas at different stages. 
      Here, we show that in late stage insulinomas, 56 genes are up-regulated and 194 
      are down-regulated more than fourfold compared with normal pancreatic islets. 
      Clustering analysis reveals the deregulation of Hox gene family and the genes 
      involved in cell proliferation and cell cycle control. The altered expression of 
      Igf2, Igfbp3 and Igfbp6 as well as cyclin A2, B2 and D2 are confirmed by 
      quantitative RT-PCR, with the overexpression of all the three cyclins found in 
      early stage insulinomas. Moreover, an increased proportion of cyclin A2- and 
      D2-expressing cells and the overexpression of insulin-like growth factor 2 (IGF2) 
      protein are detected in mouse Men1 insulinomas by immunostaining. Interestingly, 
      the analysis of DNA methylation patterns by quantitative serial pyrosequencing 
      reveals that four specific CpGs in the intragenic differentially methylated 
      region 2 (DMR2) region of the Igf2 gene known to augment transcription through 
      methylation are significantly hypermethylated in insulinomas of Men1 beta-cell 
      mutant mice at 6 and 10 months of age, even before IGF2 overexpression can be 
      detected. Thus, our data indicate the involvement of both genetic and epigenetic 
      mechanisms in early tumorigenesis of beta-cells related to MEN1 inactivation.
FAU - Fontaniere, S
AU  - Fontaniere S
AD  - Laboratoire Genetique et Cancer, CNRS, UMR5201, Faculte de Medecine, Universite 
      Claude Bernard Lyon 1, 69373 Lyon, France.
FAU - Tost, J
AU  - Tost J
FAU - Wierinckx, A
AU  - Wierinckx A
FAU - Lachuer, J
AU  - Lachuer J
FAU - Lu, J
AU  - Lu J
FAU - Hussein, N
AU  - Hussein N
FAU - Busato, F
AU  - Busato F
FAU - Gut, I
AU  - Gut I
FAU - Wang, Z-Q
AU  - Wang ZQ
FAU - Zhang, C-X
AU  - Zhang CX
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.7.- (Cre recombinase)
RN  - EC 2.7.7.- (Integrases)
SB  - IM
MH  - Animals
MH  - *DNA Methylation
MH  - Disease Models, Animal
MH  - *Epigenesis, Genetic
MH  - *Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Insulin-Secreting Cells/*metabolism/pathology
MH  - Insulinoma/*genetics/metabolism/pathology
MH  - Integrases/metabolism
MH  - Islets of Langerhans/metabolism/pathology
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Multiple Endocrine Neoplasia Type 1/*genetics
MH  - Neoplasm Proteins/genetics/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Pancreatic Neoplasms/*genetics/metabolism/pathology
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2006/12/13 09:00
MHDA- 2007/03/03 09:00
CRDT- 2006/12/13 09:00
PHST- 2006/12/13 09:00 [pubmed]
PHST- 2007/03/03 09:00 [medline]
PHST- 2006/12/13 09:00 [entrez]
AID - 13/4/1223 [pii]
AID - 10.1677/erc.1.01294 [doi]
PST - ppublish
SO  - Endocr Relat Cancer. 2006 Dec;13(4):1223-36. doi: 10.1677/erc.1.01294.