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An RNA-seq-Based Expression Profiling of Radiation-Induced Esophageal Injury in a Rat Model.

ABSTRACT: Radiation-induced acute injury is the main reason for the suspension of radiotherapy and unsuccessful treatment of cancer. It is of great importance to understand the molecular mechanism of radiation-induced esophageal injury. We used RNA-seq data from normal esophageal tissue and irradiated esophageal tissues and applied computational approaches to identify and characterize differentially expressed genes and detected 40 059 messenger RNAs (mRNAs) previously annotated and 717 novel long noncoding RNAs (lncRNAs). There were 14 upregulated and 32 downregulated lncRNAs among the differentially expressed lncRNA group. Their target genes were involved in the mRNA surveillance pathway, pathological immune responses, and cellular homeostasis. Additionally, we found 853 differentially expressed mRNAs, and there were 384 upregulated and 469 downregulated mRNAs. Notably, we found that the differentially expressed mRNAs were enriched for steroid biosynthesis, the tumor necrosis factor signaling pathway, focal adhesion, pathways in cancer, extracellular matrix-receptor interaction, and so on. The response of normal esophageal tissues to ionizing radiation is multifarious. The radiation-induced cell damage response by multiple pathways followed by pathological immune responses activated. Studies on the dynamic network of molecules involved in radiation-induced esophageal injury are under way to clarify the regulatory mechanisms and identify the candidate targets.

SUBMITTER: Sun Z

PROVIDER: S-EPMC6505253 | biostudies-literature | 2019 Apr-Jun

REPOSITORIES: biostudies-literature

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An RNA-seq-Based Expression Profiling of Radiation-Induced Esophageal Injury in a Rat Model.

Sun Zhiqiang Z Li Jinhui J Lin Min M Zhang Shuyu S Luo Judong J Tang Yiting Y

Dose-response : a publication of International Hormesis Society 20190401 2

Radiation-induced acute injury is the main reason for the suspension of radiotherapy and unsuccessful treatment of cancer. It is of great importance to understand the molecular mechanism of radiation-induced esophageal injury. We used RNA-seq data from normal esophageal tissue and irradiated esophageal tissues and applied computational approaches to identify and characterize differentially expressed genes and detected 40 059 messenger RNAs (mRNAs) previously annotated and 717 novel long noncodin ...[more]

PMID: 31105479

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Project description:PurposeExposure to radiation provokes cellular responses, which are likely regulated by gene expression networks. MicroRNAs are small non-coding RNAs, which regulate gene expression by promoting mRNA degradation or inhibiting protein translation. The expression patterns of both mRNA and miRNA during the radiation-induced lung injury (RILI) remain less characterized and the role of miRNAs in the regulation of this process has not been studied. The present study sought to evaluate miRNA and mRNA expression profiles in the rat lung after irradiation.Methods and materialsMale Wistar rats were subjected to single dose irradiation with 20 Gy using 6 MV x-rays to the right lung. (A dose rate of 5 Gy/min was applied). Rats were sacrificed at 3, 12 and 26 weeks after irradiation, and morphological changes in the lung were examined by haematoxylin and eosin. The miRNA and mRNA expression profiles were evaluated by microarrays and followed by quantitative RT-PCR analysis.ResultsA cDNA microarray analysis found 2183 transcripts being up-regulated and 2917 transcripts down-regulated (P???0.05, ?2.0 fold change) in the lung tissues after irradiation. Likewise, a miRNAs microarray analysis indicated 15 miRNA species being up-regulated and 8 down-regulated (P???0.05). Subsequent bioinformatics analyses of the differentially expressed mRNA and miRNAs revealed that alterations in mRNA expression following irradiation were negatively correlated with miRNAs expression.ConclusionsOur results provide evidence indicating that irradiation induces alterations of mRNA and miRNA expression in rat lung and that there is a negative correlation of mRNA and miRNA expression levels after irradiation. These findings significantly advance our understanding of the regulatory mechanisms underlying the pathophysiology of radiation-induced lung injury. In summary, RILI does not develop gradually in a linear process. In fact, different cell types interact via cytokines in a very complex network. Furthermore, this study suggests that microRNAs may serve an important role in the pathogenesis of RILI and that understanding their role in RILI may have a significant effect on patient management and diagnosis in the future.

Project description:Anorectal malformations (ARMs) are among the most common congenital terminal digestive tract malformations. Circular RNAs (circRNAs), a novel type of endogenous non-coding RNAs, play roles in the development of the digestive system; however, their contributions to the pathogenesis of ARMs are not well-established. In this study, we explored the mechanism underlying ethylenethiourea (ETU)-induced ARMs by profiling circRNA expression via RNA-seq and constructing a regulatory circRNA-miRNA-mRNA network. Nine pregnant rats were gavage-fed a single dose of 125 mg/kg 1% ETU (ARM group) on gestational day 10 (GD10), and another 9 pregnant rats received a similar dose of saline (normal group) as a control. Embryos were obtained by cesarean section on the key time-points of anorectal development (GD14, GD15, and GD16). Hindgut samples isolated from the fetuses were evaluated by high-throughput sequencing and differentially expressed circRNAs were validated by reverse transcription-quantitative polymerase chain reaction, agarose gel electrophoresis, and Sanger cloning and sequencing. A total of 18295 circRNAs were identified in the normal and ARM groups. Based on the 425 differentially expressed circRNAs (|Fc| > 2, p < 0.05), circRNA-miRNA and miRNA-mRNA pairs were predicted using miREAP, miRanda, and TargetScan. A total of 55 circRNAs (14 up- and 41 downregulated in the ARM group compared to the normal group) were predicted to bind to 195 miRNAs and 947 mRNAs. Competing endogenous RNA networks and a Kyoto Encyclopedia of Genes and Genomes analysis revealed that novel_circ_001042 had the greatest connectivity and was closely related to ARM-associated signaling pathways, such as the Wingless Type MMTV integration site family, mitogen-activated protein kinase, and transforming growth factor-β pathways. These results provide original insight into the roles of circRNAs in ARMs and provide a valuable resource for further analyses of molecular mechanisms and signaling networks.

Project description:UnlabelledThe UT-A1 urea transporter is crucial to the kidney's ability to generate concentrated urine. Native UT-A1 from kidney inner medulla (IM) is a heavily glycosylated protein with two glycosylation forms of 97 and 117 kDa. In diabetes, UT-A1 protein abundance, particularly the 117 kD isoform, is significantly increased corresponding to an increased urea permeability in perfused IM collecting ducts, which plays an important role in preventing the osmotic diuresis caused by glucosuria. However, how the glycan carbohydrate structure change and the glycan related enzymes regulate kidney urea transport activity, particularly under diabetic condition, is largely unknown. In this study, using sugar-specific binding lectins, we found that the carbohydrate structure of UT-A1 is changed with increased amounts of sialic acid, fucose, and increased glycan branching under diabetic conditions. These changes were accompanied by altered UT-A1 association with the galectin proteins, β-galactoside glycan binding proteins. To explore the molecular basis of the alterations of glycan structures, the highly sensitive next generation sequencing (NGS) technology, Illumina RNA-seq, was employed to analyze genes involved in the process of UT-A1 glycosylation using streptozotocin (STZ)-induced diabetic rat kidney. Differential gene expression analysis combining with quantitative PCR revealed that expression of a number of important glycosylation related genes were changed under diabetic conditions. These genes include the glycosyltransferase genes Mgat4a, the sialylation enzymes St3gal1 and St3gal4 and glycan binding protein galectin-3, -5, -8, and -9. In contrast, although highly expressed in kidney IM, the glycosyltransferase genes Mgat1, Mgat2, and fucosyltransferase Fut8, did not show any changes.ConclusionsIn diabetes, not only is UT-A1 protein abundance increased but the protein's glycan structure is also significantly changed. UT-A1 protein becomes highly sialylated, fucosylated and branched. Consistently, a number of crucial glycosylation related genes are changed under diabetic conditions. The alteration of these genes may contribute to changes in the UT-A1 glycan structure and therefore modulate kidney urea transport activity and alleviate osmotic diuresis caused by glucosuria in diabetes.

Dataset Information

An RNA-seq-Based Expression Profiling of Radiation-Induced Esophageal Injury in a Rat Model.

Publications

An RNA-seq-Based Expression Profiling of Radiation-Induced Esophageal Injury in a Rat Model.

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