Abstract
In the human genome, there are about 600 ultra-conserved regions (UCRs), long DNA sequences extremely conserved in vertebrates. We performed a large-scale study to quantify transcribed UCR (T-UCR) and miRNA levels in over 6000 cancer and normal tissue samples to find possible correlation between these kinds of regulatory molecules. Our analysis evidenced several non-coding RNAs showing negative co-regulation with miRNAs; among them, we focused on miR-221 to investigate any relationship with its pivotal role in the cell cycle. We have chosen breast cancer as model, using two cell lines with different phenotypes to carry out in vitro treatments with siRNAs against T-UCRs. Our results demonstrate that the expression of uc.183, uc.110, and uc.84 T-UCRs is mutually exclusive with miR-221 and is engaged in the regulation of CDKN1B expression. In addition, tests with a set of anticancer drugs, including BYL719, AZD5363, AZD8055, AZD7762, and XL765, revealed the modulation of specific T-UCRs without alteration of miR-221 levels.
Highlights
Non-coding RNAs represent a large portion of the human genome which are not translated into proteins mediating transcriptional gene modulation [1]
We further investigated the T-ultra-conserved regions (UCRs)’ expression upon treatments of breast cancer (BC) cell lines using anticancer drugs, which led to the identification of an alternative modulation of miR-221 and transcribed UCR (T-UCR)
We studied the expression of T-UCRs and miRNAs in 6604 samples, derived from cancer and control tissues, using the Ohio State University Comprehensive Cancer Center (OSUCCC) custom microarray [8,23]
Summary
Non-coding RNAs (ncRNAs) represent a large portion of the human genome which are not translated into proteins mediating transcriptional gene modulation [1]. The class of Ultra-conserved regions (UCRs) are DNA elements of more than 200 base pairs long, without insertion or deletion and extremely conserved in the orthologous loci of vertebrates, in particular human [3], mouse, and rat genomes [4], but Single Nucleotide Polymorphisms (SNPs) in UCRs are related to cancer susceptibility [5] Their expression is altered in leukemia [6], liver cancer [7], glioma [8], and neuroblastoma [9], which might be modulated either by promoter hyper-methylation or by interactions with microRNAs (miRNAs) [10]. One T-UCR seems to regulate apoptosis [22]; in the literature, there are few reports about the influence of other T-UCRs in this cellular program
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