Khalafiyan Anis, Emadi-Baygi Modjtaba, Wolfien Markus, Salehzadeh-Yazdi Ali, Nikpour Parvaneh
Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran.
J Cell Biochem. 2023 Mar;124(3):396-408. doi: 10.1002/jcb.30373. Epub 2023 Feb 7.
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.
转录超保守区域（T-UCRs）作为在人类、小鼠和大鼠基因组之间具有100%保守性的基因组序列，其在肿瘤病理生理学中的表达改变和功能作用已得到研究。然而，T-UCRs在胃癌（GC）中的功能相关性仍是研究的课题。在当前研究中，我们首先使用全基因组分析方法来分析GC患者中T-UCRs的表达。然后，我们构建了一个三组分调控网络，并研究了T-UCRs的潜在诊断和预后价值。癌症基因组图谱胃腺癌（TCGA-STAD）数据集用作RNA测序数据的来源。使用FeatureCounts来量化映射到每个T-UCR的读数数量。然后使用DESeq2进行差异表达分析。接下来，将T-UCRs、微小RNA（miRNAs）和信使RNA（mRNAs）之间的相互作用组合成一个三组分网络。进行了富集分析并构建了蛋白质-蛋白质相互作用（PPI）网络。使用R生存软件包来鉴定与生存相关的显著差异表达的T-UCRs（DET-UCRs）。使用GC组织的内部队列，进一步通过实验验证了两个DET-UCRs的表达。我们的结果表明，与非肿瘤对应物相比，TCGA-STAD肿瘤样本中几个T-UCRs的表达失调。构建了由DET-UCRs、miRNAs和mRNAs节点组成的三组分网络。功能富集和PPI网络分析揭示了重要的富集信号通路和基因本体，如“癌症通路”以及细胞增殖和凋亡的调节。五个T-UCRs与GC患者的总生存期显著相关。虽然在我们的GC组织内部队列中未观察到uc.232的表达，但uc.343在胃肿瘤组织中显示出表达增加，尽管无统计学意义。构建的GC中T-UCRs的三组分调控网络提供了对肿瘤发生中潜在基因表达调控过程的全面理解，并可作为研究潜在预后生物标志物和治疗靶点的基础。
