Role of Peroxisome Proliferator-Activated Receptor and B-Cell Lymphoma-6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells
PPAR / 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 PPAR / 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 PPAR / , and lower levels of BCL-6 mRNA. PPAR / activation reduced the TNFα-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 PPAR / , BCL-6, and MMP-9, it was evident that PPAR / 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 PPAR / 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. 1. Introduction Pancreatic cancer is the fourth leading cause of cancer-related deaths of men and women in the United States. The American Cancer Society estimates for 2009 predicted approximately 42,470 new cases of pancreatic cancer and that 35,240 of those cases would result in death. Lack of identifiable symptoms or biomarkers combined with a 4% five-year survival rate makes pancreatic cancer one of the deadliest malignancies [1]. Although pancreatic cancer is difficult to detect in its early stages, several known risk factors exist, with smoking being the most well-documented etiologic agent [2]. Several other risk factors include age, diets high in fat [3], excessive alcohol consumption [4], diabetes mellitus [5], and chronic pancreatitis [6]. Common chemotherapeutic treatments have had little success in improving survival rates or restraining the highly metastatic malignancies [7] with the median survival rate of less than six months and surgical resection as the only effective treatment [8]. Prevention strategies and alternative treatments for pancreatic cancer are sorely needed. Peroxisome proliferator-activated receptor- ( ) is a member of the nuclear receptor
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