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

• Published in: Journal of cellular biochemistry Vol. 124; no. 3; pp. 396 - 408
• Main Authors: Khalafiyan, Anis, Emadi‐Baygi, Modjtaba, Wolfien, Markus, Salehzadeh‐Yazdi, Ali, Nikpour, Parvaneh
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2023
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Animals; Apoptosis; Biomarkers; Biomarkers, Tumor - genetics; Cancer; Cell proliferation; Conserved sequence; Conserved Sequence - genetics; Enrichment; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Gene Regulatory Networks; Gene sequencing; Genomes; Humans; long noncoding RNA (lncRNA); Mice; MicroRNAs; MicroRNAs - genetics; miRNA; Neoplasms; Prognosis; Proteins; Rats; RNA, Long Noncoding; Statistical analysis; stomach cancer; Stomach Neoplasms - genetics; Survival; The Cancer Genome Atlas (TCGA); Therapeutic targets; transcribed ultraconserved regions (T‐UCRs); long noncoding RNA (lncRNA); transcribed ultraconserved regions (T-UCRs); stomach cancer; The Cancer Genome Atlas (TCGA)
• ISSN: 0730-2312; 1097-4644; 1097-4644
• DOI: 10.1002/jcb.30373

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 three‐component 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 T‐UCRs in GC presents a comprehensive understanding of the underlying gene expression regulation processes involved in tumor development and can serve as a basis to investigate potential prognostic biomarkers and therapeutic targets.