Construction of a three‐component regulatory network of transcribed ultraconserved regions for the identification of prognostic biomarkers in gastric cancer

Abstract

Altered expression and functional roles of the transcribed ultraconserved regions (T-UCRs), as genomic sequences with 100% conservation between the genomes of human, mouse, and rat, in the pathophysiology of neoplasms has already been investigated. Nevertheless, the relevance of the functions for T-UCRs in gastric cancer (GC) is still the subject of inquiry. In the current study, we first used a genome-wide profiling approach to analyze the expression of T-UCRs in GC patients. Then, we constructed a threecomponent regulatory network and investigated potential diagnostic and prognostic values of the T-UCRs. The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) dataset was used as a resource for the RNA-sequencing data. FeatureCounts was utilized to quantify the number of reads mapped to each T-UCR. Differential expression analysis was then conducted using DESeq2. In the following, interactions between T-UCRs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were combined into a three-component network. Enrichment analyses were performed and a protein-protein interaction (PPI) network was constructed. The R Survival package was utilized to identify survival-related significantly differentially expressed T-UCRs (DET-UCRs). Using an in-house cohort of GC tissues, expression of two DET-UCRs was furthermore experimentally verified. Our results showed that several T-UCRs were dysregulated in TCGA-STAD tumoral samples compared to nontumoral counterparts. The three-component network was constructed which composed of DET-UCRs, miRNAs, and mRNAs nodes. Functional enrichment and PPI network analyses revealed important enriched signaling pathways and gene ontologies such as "pathway in cancer" and regulation of cell proliferation and apoptosis. Five T-UCRs were significantly correlated with the overall survival of GC patients. While no expression of uc.232 was observed in our in-house cohort of GC tissues, uc.343 showed an increased expression, although not statistically significant, in gastric tumoral tissues. The constructed three-component regulatory network of

Transcribed-Ultra Conserved Regions (T-UCRs) a New Light on a Dark Matter

“…Examining the functions of T-UCRs individually and searching for a single target for one T-UCR is an approach that is increasingly being replaced by more complex ones, such as constructing three-component regulatory networks-T-UCRs-miRNAs-mRNAs. Simultaneously tracking multiple T-UCR interactions within a single disease allows for the evaluation of the potential diagnostic and prognostic values of T-UCRs, as demonstrated in the study by Khalafiyan et al, where five T-UCRs including uc.8, uc.169, uc.342, uc.360, and uc.417 were found to be correlated with the overall survival of gastric cancer patients [95]. On the other hand, three-component regulatory networks provide an opportunity for a comprehensive understanding of the underlying gene expression regulation processes involved in pathogenesis.…”