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PLoS One. 2018 Jan 4;13(1):e0190708. doi: 10.1371/journal.pone.0190708. eCollection 2018.

The effects of alternative splicing on miRNA binding sites in bladder cancer.

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Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Department of Biomedical & Translational Informatics, Geisinger Health System, Danville, Pennsylvania, United States of America.
Department of Biomedical Informatics, School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Mowad Urology Department, Geisinger Health System, Danville, Pennsylvania, United States of America.
Seoul National University Biomedical Informatics, Seoul, South Korea.


Eukaryotic organisms have developed a variety of mechanisms to regulate translation post-transcriptionally, including but not limited to the use of miRNA silencing in many species. One method of post-transcriptional regulation is through miRNAs that bind to the 3' UTRs to regulate mRNA abundance and influence protein expression. Therefore, the diversity of mRNA 3' UTRs mediating miRNA binding sites influence miRNA-mediated regulation. Alternative polyadenylation, by shortening mRNA isoforms, increases the diversity of 3' UTRs; moreover, short mRNA isoforms elude miRNA-medicated repression. Because no current prediction methods for putative miRNA target sites consider whether or not 1) splicing-informed miRNA binding sites and/or 2) the use of 3' UTRs provide higher resolution or functionality, we sought to identify not only the genome-wide impact of using exons in mRNA 3' UTRs but also their functional connection to miRNA regulation and clinical outcomes in cancer. With a genome-wide expression of mRNA and miRNA quantified by 395 bladder cancer cases from The Cancer Genome Atlas (TCGA), we 1) demonstrate the diversity of 3' UTRs affecting miRNA efficiency and 2) identify a set of genes clinically associated with mRNA expression in bladder cancer. Knowledge of 3' UTR diversity will not only be a useful addition to current miRNA target prediction algorithms but also enhance the clinical utility of mRNA isoforms in the expression of mRNA in cancer. Thus, variability among cancer patient's variability in molecular signatures based on these exon usage events in 3' UTR along with miRNAs in bladder cancer may lead to better prognostic/treatment strategies for improved precision medicine.

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