Abstract
In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p) was selected for further studies. A strong correlation was observed for six of the seven miRNAs in 43 advanced tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both the BxPC3-GZR model and advanced PDAC tumor specimens. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13). Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread.
Highlights
pancreatic ductal adenocarcinoma (PDAC) continues to have the worst prognosis of any solid tumor
Generation of a pancreatic cancer chemoresistant and a mesenchymal phenotype (CRMP) cell line model The PDAC cell line BxPC3 was transiently exposed to increasing concentrations of gemcitabine over a six-week period
Recent evidence indicates a link between chemoresistance and metastatic potential of cancer cells that possess an epithelial to mesenchymal transition (EMT) phenotype and express stem cell markers [36]
Summary
PDAC continues to have the worst prognosis of any solid tumor. In 2013, it is estimated that more than 45,000 new cases will be diagnosed in the United States with mortality to incidence ratio almost equal to one [1]. Many PDAC are initially resistant to gemcitabine and responsive ones generally develop resistance during the course of treatment [3]. It remains to be determined whether the chemoresistant phenotype is induced as a result of therapy or whether there is a subpopulation of cancer cells within the tumor that are innately more resistant to therapy. Recent evidence indicates that most solid tumors, including PDAC possess a distinct subpopulation of cancer stem cells (CSCs). Evidence suggests that CSCs are inherently more resistant to chemotherapy and utilize their self-renewal potential to regenerate new tumor growth [4]. A previous study links CSCs with epithelial to mesenchymal transition (EMT) [5]
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