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.

Published onlineJOURNAL ARTICLEMice 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-KRAS(G12D) as well as PDX-1-Cre;LSL-KRAS(G12D) mice. One hundred of the differentially expressed miRNAs had increased expression in the advanced disease (old) P48(+/Cre);LSL-KRAS(G12D) compared 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-Kras(G12D) mouse 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 Kras(G12D) transgenic mice and report lethality from deletion of the miR-216/-217 host gene in the mouse's germ line.This work was supported by a Pelotonia idea grant from the Ohio State University to T.D.S. and E.C. A.C.P.A.P. was supported by NIH fellowship 5F31CA142238. We thank Dr. David Tuveson for providing the RNA samples from the KC and control mice. We thank Dr. Caifu Chen for his assistance with the mouse TaqMan miRNA assays and Luke Bramlage and Andrea Haughtvedt for their technical assistance. We also thank Inga Carsten of the Genetically Engineered Mouse Modeling Core for the help in mES microinjection