title: Frequent methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene in pancreatic endocrine tumors.
abstract: Molecular mechanisms contributing to the tumorigenesis of pancreatic endocrine tumors (PETs) are still not well understood. Allelic deletions at chromosome 22q12.3 were detected in about 30-60% of PETs, suggesting that inactivation of one or more tumor suppressor genes on this chromosomal arm is important for their pathogenesis. Because the putative tumor suppressor gene tissue inhibitor of metalloproteinase-3 (TIMP-3) has been located at 22q12.3, we undertook a genetic analysis of TIMP-3 to determine its role in the tumorigenesis of PETs. Single-strand conformational polymorphism analysis, methylation-specific PCR, RNA expression analysis, and immunohistochemistry of TIMP-3 were performed in 21 sporadic PETs. Thirteen of 21 PETs (62%) revealed TIMP-3 alterations, including promoter hypermethylation and homozygous deletion. The predominant TIMP-3 alteration was promoter hypermethylation, identified in 8 of 18 (44%) PETs. It was tumor-specific and corresponded to loss or strong reduction of TIMP-3 protein expression. Notably, 11 of 14 (79%) PETs with metastases had TIMP-3 alterations, compared with only 1 of 7 (14%) PETs without metastases (P < 0.02). These data suggest a possibly important role of TIMP-3 in the tumorigenesis of human PETs, especially in the development of metastases, which has to be further evaluated in large-scale studies.
authors.affiliation: Department of Surgery, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Wild
authors.forename: Annette
authors.initials: A
authors.lastname: Ramaswamy
authors.forename: Peter
authors.initials: P
authors.lastname: Langer
authors.forename: Ilhan
authors.initials: I
authors.lastname: Celik
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Chaloupka
authors.forename: Babette
authors.initials: B
authors.lastname: Simon
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
mesh_terms: D019175:DNA Methylation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D019717:Tissue Inhibitor of Metalloproteinase-3