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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

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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-KRASG12D as well as PDX-1-Cre;LSL-KRASG12D mice. One hundred of the differentially expressed miRNAs had increased expression in the advanced disease (old) P48+/Cre;LSL-KRASG12D 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-KrasG12D 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 KrasG12D transgenic mice and report lethality from deletion of the miR-216/-217 host gene in the mouse’s germ line.

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Acknowledgments

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.

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  1. Ana Clara P. Azevedo-Pouly

    Present address: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Authors and Affiliations

  1. College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Ana Clara P. Azevedo-Pouly, Dhruvitkumar S. Sutaria & Ola A. Elgamal

  2. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Jinmai Jiang & Thomas D. Schmittgen

  3. College of Medicine, The Ohio State University, Columbus, OH, USA

    Foued Amari & Vincenzo Coppola

  4. Cambridge University, Cambridge, UK

    David Allard

  5. Department of Medicine, University of Illinois Chicago, Chicago, IL, USA

    Paul J. Grippo

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  1. Ana Clara P. Azevedo-Pouly
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Correspondence to Thomas D. Schmittgen.

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This article forms part of a special issue of Functional & Integrative Genomics entitled “miRNA in model and complex organisms” (Issue Editors: Hikmet Budak and Baohong Zhang).

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Azevedo-Pouly, A.C.P., Sutaria, D.S., Jiang, J. et al. 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. Funct Integr Genomics 17, 203–212 (2017). https://doi.org/10.1007/s10142-016-0512-1

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