title: Role of Peroxisome Proliferator-Activated Receptor β/δ and B-Cell Lymphoma-6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells.
abstract: PPARβ/δ is a ligand-activated transcription factor that regulates various cellular functions via induction of target genes directly or in concert with its associated transcriptional repressor, BCL-6. Matrix remodeling proteinases are frequently over-expressed in pancreatic cancer and are involved with metastasis. The present study tested the hypothesis that PPARβ/δ is expressed in human pancreatic cancer cells and that its activation could regulate MMP-9, decreasing cancer cells ability to transverse the basement membrane. In human pancreatic cancer tissue there was significantly higher expression of MMP-9 and PPARβ/δ, and lower levels of BCL-6 mRNA. PPARβ/δ activation reduced the TNF α -induced expression of various genes implicated in metastasis and reduced the invasion through a basement membrane in cell culture models. Through the use of short hairpin RNA inhibitors of PPARβ/δ, BCL-6, and MMP-9, it was evident that PPARβ/δ was responsible for the ligand-dependent effects whereas BCL-6 dissociation upon GW501516 treatment was ultimately responsible for decreasing MMP-9 expression and hence invasion activity. These results suggest that PPARβ/δ plays a role in regulating pancreatic cancer cell invasion through regulation of genes via ligand-dependent release of BCL-6 and that activation of the receptor may provide an alternative therapeutic method for controlling migration and metastasis.
authors.affiliation: Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, Penn State University, 325 Life Sciences Building, University Park, PA 16802, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Coleman
authors.forename: Jerry T
authors.initials: JT
authors.lastname: Thompson
authors.forename: Russell W
authors.initials: RW
authors.lastname: Smith
authors.forename: Bogdan
authors.initials: B
authors.lastname: Prokopczyk
authors.forename: John P
authors.initials: JP
authors.lastname: Vanden Heuvel