Globally increased ultraconserved noncoding RNA expression in pancreatic adenocarcinoma

Abstract

// Jinmai Jiang 1, * , Ana Clara P. Azevedo-Pouly 2, 8, * , Roxana S. Redis 3, * , Eun Joo Lee 2, 9 , Yuriy Gusev 4 , David Allard 5 , Dhruvitkumar S. Sutaria 2 , Mohamed Badawi 2 , Ola A. Elgamal 2 , Megan R. Lerner 6, 7 , Daniel J. Brackett 6, 7 , George A. Calin 3 , Thomas D. Schmittgen 1 1 College of Pharmacy, University of Florida, Gainesville, FL, USA 2 College of Pharmacy, Ohio State University, Columbus, OH, USA 3 University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 4 Lombardi Cancer Center, Georgetown University, Washington, DC, USA 5 Cambridge University, Cambridge, UK 6 Veterans Affairs Medical Center, Oklahoma City, OK, USA 7 Department of Surgery, University of Oklahoma Health Science Center, Oklahoma City, OK, USA 8 Present address: Department of Molecular Biology University of Texas Southwestern Medical Center, Dallas, TX, USA 9 Present address: College of Pharmacy and Wonkwang Oriental Medicines Research Institute, Wonkwang University, Republic of Korea * These authors have contributed equally to this work Correspondence to: Thomas D. Schmittgen, email: [e-mail] Keywords: noncoding RNA, ultraconserved elements, EGR1, pancreas cancer Received: November 19, 2015     Accepted: May 28, 2016     Published: June 23, 2016 ABSTRACT 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 P48 Cre/wt ; Kras LSL-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.