Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model
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Satyanarayana Rachagani1, Muzafar A. Macha1,*, Melanie S. Menning1,*, Parama Dey1, Priya Pai1, Lynette M. Smith2, Yin-Yuan Mo5, Surinder K. Batra1,3,4
1Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
2Department of Biostatistics, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
3Department of Pathology and Microbiology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
4Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
5Department of Pharmacology and Toxicology, University of Mississippi Medical center, Jackson, MS, USA
*These authors have contributed equally to this work
Satyanarayana Rachagani, e-mail: firstname.lastname@example.org
Surinder K. Batra, e-mail: email@example.com
Keywords: miRNA, pancreatic cancer, KC mouse model
Received: May 11, 2015 Accepted: October 09, 2015 Published: October 19, 2015
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.
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