title: A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.
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.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Alakesh
authors.initials: A
authors.lastname: Bera
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Kolaparthi
authors.initials: K
authors.lastname: VenkataSubbaRao
authors.affiliation: Research and Development, Audie Murphy Veterans Administration Hospital, San Antonio, Texas, United States of America.
authors.forename: Muthu Saravanan
authors.initials: MS
authors.lastname: Manoharan
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Hill
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Cancer Therapy and Research Center, Experimental and Developmental Therapeutics Program, San Antonio, Texas, United States of America; Research and Development, Audie Murphy Veterans Administration Hospital, San Antonio, Texas, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Freeman
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009439:Neuraminidase / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D003841:Deoxycytidine; C486385:NEU1 protein, human; D009439:Neuraminidase; D000093542:Gemcitabine