Role of Peroxisome Proliferator-Activated Receptor beta/delta and B-Cell Lymphoma-6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells.
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Coleman JD, Thompson JT, Smith RW 3rd, Prokopczyk B, Vanden Heuvel JP
Role of Peroxisome Proliferator-Activated Receptor beta/delta and B-Cell Lymphoma-6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells.
PPAR Res. 2013;2013:121956. doi: 10.1155/2013/121956. Epub 2013 May 2.
- PubMed ID
- 23737761 [ View in PubMed]
- Abstract
PPARbeta/delta 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 PPARbeta/delta 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 PPARbeta/delta, and lower levels of BCL-6 mRNA. PPARbeta/delta activation reduced the TNF alpha -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 PPARbeta/delta, BCL-6, and MMP-9, it was evident that PPARbeta/delta 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 PPARbeta/delta 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.