title: Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.
abstract: Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets.
authors.affiliation: Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Muzafar A
authors.initials: MA
authors.lastname: Macha
authors.affiliation: Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Menning
authors.affiliation: Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Parama
authors.initials: P
authors.lastname: Dey
authors.affiliation: Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Pai
authors.affiliation: Department of Biostatistics, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical center, Jackson, MS, USA.
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
authors.affiliation: Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.|Department of Pathology and Microbiology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.|Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering / Q000379:methods; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; D015534:Trans-Activators; C487931:mirnlet7 microRNA, human; C084010:pancreatic and duodenal homeobox 1 protein; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KC mouse model; miRNA; pancreatic cancer