Globally increased ultraconserved noncoding RNA expression in pancreatic adenocarcinoma
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Jinmai Jiang1,*, Ana Clara P. Azevedo-Pouly2,8,*, Roxana S. Redis3,*, Eun Joo Lee2,9, Yuriy Gusev4, David Allard5, Dhruvitkumar S. Sutaria2, Mohamed Badawi2, Ola A. Elgamal2, Megan R. Lerner6,7, Daniel J. Brackett6,7, George A. Calin3, Thomas D. Schmittgen1
1College of Pharmacy, University of Florida, Gainesville, FL, USA
2College of Pharmacy, Ohio State University, Columbus, OH, USA
3University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
4Lombardi Cancer Center, Georgetown University, Washington, DC, USA
5Cambridge University, Cambridge, UK
6Veterans Affairs Medical Center, Oklahoma City, OK, USA
7Department of Surgery, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
8Present address: Department of Molecular Biology University of Texas Southwestern Medical Center, Dallas, TX, USA
9Present address: College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Republic of Korea
*These authors have contributed equally to this work
Thomas D. Schmittgen, email: firstname.lastname@example.org
Keywords: noncoding RNA, ultraconserved elements, EGR1, pancreas cancer
Received: November 19, 2015 Accepted: May 28, 2016 Published: June 23, 2016
Transcribed ultraconserved regions (T-UCRs) are a class of non-coding RNAs with 100% sequence conservation among human, rat and mouse genomes. T-UCRs are differentially expressed in several cancers, however their expression in pancreatic adenocarcinoma (PDAC) has not been studied. We used a qPCR array to profile all 481 T-UCRs in pancreatic cancer specimens, pancreatic cancer cell lines, during experimental pancreatic desmoplasia and in the pancreases of P48Cre/wt; KrasLSL-G12D/wt mice. Fourteen, 57 and 29% of the detectable T-UCRs were differentially expressed in the cell lines, human tumors and transgenic mouse pancreases, respectively. The vast majority of the differentially expressed T-UCRs had increased expression in the cancer. T-UCRs were monitored using an in vitro model of the desmoplastic reaction. Twenty-five % of the expressed T-UCRs were increased in the HPDE cells cultured on PANC-1 cellular matrix. UC.190, UC.233 and UC.270 were increased in all three human data sets. siRNA knockdown of each of these three T-UCRs reduced the proliferation of MIA PaCa-2 cells up to 60%. The expression pattern among many T-UCRs in the human and mouse pancreases closely correlated with one another, suggesting that groups of T-UCRs are co-activated in PDAC. Successful knockout of the transcription factor EGR1 in PANC-1 cells caused a reduction in the expression of a subset of T-UCRs suggesting that EGR1 may control T-UCR expression in PDAC. We report a global increase in expression of T-UCRs in both human and mouse PDAC. Commonalties in their expression pattern suggest a similar mechanism of transcriptional upregulation for T-UCRs in PDAC.
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