Abstract A81: A microRNA signature identified for chemoresistance and mesenchymal phenotype is also found in advanced pancreatic cancer

Abstract

Abstract Recent studies link cancer cells that possess an epithelial to mesenchymal transition (EMT) and cancer stem cell properties with chemoresistance and metastatic potential. Here, we investigated the molecular bases of the chemoresistant mesenchymal phenotype (CRMP) with emphasis on identifying a micro-RNA (miRNA) signature in advanced pancreatic ductal adenocarcinoma (PDAC). We developed a gemcitabine resistant cell model from a PDAC cell line, BxPC3. This gemcitabine resistant cell line (BxPC3-GZR) showed a pronounced mesenchymal phenotype and expressed high levels of CD44 a marker found on stem cells and showed a highly significant increase in expression of nine miRNAs and decrease in eight miRNAs. Based on relevance to cancer and on validation by q-RT-PCR we chose six of the miRNAs (miR-100, miR-125b, miR-21, miR-205, miR-27b and miR-455-3p) as a signature to determine whether they were similarly deregulated in 43 advanced PDAC tumor specimens previously analyzed as part of the Total Cancer Genome Atlas (TCGA). A strong correlation was observed for five of the six miRNAs in the tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both cellular CRMP and advanced PDAC. 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. The results of this study suggests that CRMP is caused in part by deregulation of a specific set of miRNAs and that these miRNAs are also deregulated in advanced PDAC. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread. Citation Format: James W. Freeman, Alakesh Bera, Venkatasubbarao Kolaparthi. A microRNA signature identified for chemoresistance and mesenchymal phenotype is also found in advanced pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A81.