title: miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal.
abstract: Mice harboring a G12D activating Kras mutation are among the most heavily studied models in the field of pancreatic adenocarcinoma (PDAC) research. miRNAs are differentially expressed in PDAC from patients and mouse models of PDAC. To better understand the relationship that Kras activation has on miRNA expression, we profiled the expression of 629 miRNAs in RNA isolated from the pancreas of control, young, and old P48+/Cre;LSL-KRASG12Das well as PDX-1-Cre;LSL-KRASG12Dmice. One hundred of the differentially expressed miRNAs had increased expression in the advanced disease (old) P48+/Cre;LSL-KRASG12Dcompared to wild-type mice. Interestingly, the expression of three miRNAs, miR-216a, miR-216b, and miR-217, located within a ∼30-kbp region on 11qA3.3, decreased with age (and phenotype severity) in these mice. miR-216/-217 expression was also evaluated in another acinar-specific ELa-KrasG12Dmouse model and was downregulated as well. As miR-216/-217 are acinar enriched, reduced in human PDAC and target KRAS, we hypothesized that they may maintain acinar differentiation or represent tumor suppressive miRNAs. To test this hypothesis, we deleted a 27.9-kbp region of 11qA3.3 containing the miR-216/-217 host gene in the mouse's germ line. We report that germ line deletion of this cluster is embryonic lethal in the mouse. We estimate that lethality occurs shortly after E9.5. qPCR analysis of the miR-216b and miR-217 expression in the heterozygous animals showed no difference in expression, suggesting haplosufficiency by some type of compensatory mechanism. We present the differential miRNA expression in KrasG12Dtransgenic mice and report lethality from deletion of the miR-216/-217 host gene in the mouse's germ line.
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Ana Clara P
authors.initials: AC
authors.lastname: Azevedo-Pouly
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Dhruvitkumar S
authors.initials: DS
authors.lastname: Sutaria
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Jinmai
authors.initials: J
authors.lastname: Jiang
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Ola A
authors.initials: OA
authors.lastname: Elgamal
authors.affiliation: College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Foued
authors.initials: F
authors.lastname: Amari
authors.affiliation: Cambridge University, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Allard
authors.affiliation: Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.affiliation: College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. tschmittgen@ufl.edu.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Schmittgen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D005804:Genes, Lethal; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*
chemical_list: C000591813:MIRN-217 microRNA, mouse; C553402:MIRN216 microRNA, mouse; D035683:MicroRNAs
keywords: Kras; Pancreatic cancer; Transgenic mice; lncRNA; miR-216a; miR-216b; miR-217; microRNA