Tissue and exosomal miRNA editing in Non-Small Cell Lung Cancer

Nigita, Giovanni; Distefano, Rosario; Veneziano, Dario; Romano, Giulia; Mohammad, Rahman; Wang, Kai; Pass, Harvey I.; Croce, Carlo M.; Acunzo, Mario; Nana‐Sinkam, Patrick

doi:10.1038/s41598-018-28528-1

Cited by 41 publications

(48 citation statements)

References 42 publications

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“…In consistent with our research, Soundararajan et al identi ed 652 editing events in lung cancer, which were located in the 3´UTR of 205 target genes and mapped to 932 potential microRNA target binding sites [92]. All together these ndings are inconsistent with Liang [96]. Indeed, our results showed miR-34a, a cancer-speci c edited microRNA, was edited in 10 position.…”

Section: Discussionsupporting

confidence: 85%

Comprehensive Characterization of RNA Editing in Primary Gastric Adenocarcinoma through RNA-seq Data Analysis

Behroozi

Shahbazi²,

Bakhtiarizadeh

et al. 2020

Preprint

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RNA editing is a post-transcriptional nucleotide modification in humans. Of the various types of RNA editing, the adenosine to inosine substitution is the most widespread in higher eukaryotes, which is mediated by ADAR family enzyme. Inosine is recognized by the biological machineries as guanosine, therefore, editing can potentially rendering substantial functional effects throughout the genome, depending on where it located. RNA editing could contribute to cancer by either exclusive editing of tumor suppressor/promoting genes or by introducing transcriptomic diversity to promote cancer progression. Here, we provided a comprehensive overview of the RNA editing sites in gastric adenocarcinoma and highlighted some of their possible contributions to gastric cancer. RNA-seq data corresponding to 8 gastric adenocarcinoma and their paired non-tumor counterparts were retrieved from GEO database. After pre-possessing and variant calling steps, a stringent filtering pipeline was employed to distinguish potential RNA editing sites from SNPs. The identified potential editing sites were annotated and compared with those in DARNED database. Totally, 12362 high-confidence adenosine to inosine RNA editing sites were detected across all samples. Of these, 12105 and 257 were known and novel editing events, respectively. These editing sites were unevenly distributed across genomic regions, nearly half of them were located in 3´UTR. Indeed, 4868, 3985 and 3509 editing sites were found to be common in both tissue, normal specific and cancer specific, respectively. Further analysis revealed significant number of differentially edited events among these sites, which were located in protein coding genes and microRNAs. Given the distinct pattern of RNA editing in gastric adenocarcinoma and adjacent normal tissue, edited sites have the potential to serve as biomarkers and therapeutic targets in gastric cancer diagnose, management and treatment.

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Section: Discussionsupporting

confidence: 85%

Comprehensive Characterization of RNA Editing in Primary Gastric Adenocarcinoma through RNA-seq Data Analysis

Behroozi

Shahbazi²,

Bakhtiarizadeh

et al. 2020

Preprint

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“…All the six edited sites have preferable sequence motifs for ADAR enzymes, which is (1) over-represented uridine (U) but depleted guanosine (G) at the nucleotides before the edited sites and (2) over-represented guanosine at the nucleotides after the edited sites. Confidence of edited site (Li et al, 2018) reported in brain (Alon et al, 2012) and reported in exosomes (Nigita et al, 2018).…”

Section: Select A-to-i Editing In Exosome-enriched Fraction Mirnasmentioning

confidence: 54%

“…All the edited sites have been reported as "confident" in a recent comprehensive analysis profiling ADAR editing (Li et al, 2018). In addition, three of them (miR-411-5p at position 5, miR-376b-3p at position 6, and miR-421-3p at position 14) have been reported in brain (Alon et al, 2012), with comparable editing levels, while miR-411-5p (at position 5) has been reported in plasma-derived exosomes (Nigita et al, 2018). Moreover, they all have preferable sequence motifs for ADARs, which is uridine (U) enriched and guanosine (G) depleted at the nucleotide preceding the edited sites (four U and zero G out of six) and guanosine enriched at the nucleotides following the edited sites (five out of six) (Figure 8).…”

Section: Select A-to-i Editing In Exosome-enriched Fraction Mirnasmentioning

confidence: 91%

“…Little is known about the role or function of exosomal miRNAs and their editing in epilepsy. Altered expression of miRNAs has been reported within exosomes recovered from blood samples in patients with temporal lobe epilepsy (Yan et al, 2017) and dysregulation of miRNA editing has been reported in exosomes in non-CNS disease (Nigita et al, 2018). We recently found that cerebrospinal fluid from patients who experienced status epilepticus displayed different exosome miRNA content compared to other neurological diseases (Raoof et al, 2017).…”

Section: Introductionmentioning

confidence: 98%

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Altered Biogenesis and MicroRNA Content of Hippocampal Exosomes Following Experimental Status Epilepticus

et al. 2020

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Repetitive or prolonged seizures (status epilepticus) can damage neurons within the hippocampus, trigger gliosis, and generate an enduring state of hyperexcitability. Recent studies have suggested that microvesicles including exosomes are released from brain cells following stimulation and tissue injury, conveying contents between cells including microRNAs (miRNAs). Here, we characterized the effects of experimental status epilepticus on the expression of exosome biosynthesis components and analyzed miRNA content in exosome-enriched fractions. Status epilepticus induced by unilateral intra-amygdala kainic acid in mice resulted in acute subfield-specific, bidirectional changes in hippocampal transcripts associated with exosome biosynthesis including up-regulation of endosomal sorting complexes required for transport (ESCRT)dependent and-independent pathways. Increased expression of exosome components including Alix were detectable in samples obtained 2 weeks after status epilepticus and changes occurred in both the ipsilateral and contralateral hippocampus. RNA sequencing of exosome-enriched fractions prepared using two different techniques detected a rich diversity of conserved miRNAs and showed that status epilepticus selectively alters miRNA contents. We also characterized editing sites of the exosomeenriched miRNAs and found six exosome-enriched miRNAs that were adenosine-toinosine (ADAR) edited with the majority of the editing events predicted to occur within miRNA seed regions. However, the prevalence of these editing events was not altered by status epilepticus. These studies demonstrate that status epilepticus alters the exosome pathway and its miRNA content, but not editing patterns. Further functional studies will be needed to determine if these changes have pathophysiological significance for epileptogenesis.

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“…In addition to expression level analysis, variation in sequences, such as RNA editing, can also be detected by the RNA-seq method. Very recently, Nigita et al found that miRNA editing events also occur in blood circulation, and the analysis of exosomal edited cargo was able to distinguish between normal and tumor sample subtypes [66]. In MDS, a pilot study on RNA editing was published by Crews et al, who showed that A-to-I RNA editing rates were increased in AML-MRC compared to MDS progenitors and that the differential expression of certain sites was as high as 70% [67].…”

Section: Discussionmentioning

confidence: 99%

Circulating Small Noncoding RNAs Have Specific Expression Patterns in Plasma and Extracellular Vesicles in Myelodysplastic Syndromes and Are Predictive of Patient Outcome

Hruštincová

Krejčík

Kundrat

et al. 2020

Cells

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Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders with large heterogeneity at the clinical and molecular levels. As diagnostic procedures shift from bone marrow biopsies towards less invasive techniques, circulating small noncoding RNAs (sncRNAs) have become of particular interest as potential novel noninvasive biomarkers of the disease. We aimed to characterize the expression profiles of circulating sncRNAs of MDS patients and to search for specific RNAs applicable as potential biomarkers. We performed small RNA-seq in paired samples of total plasma and plasma-derived extracellular vesicles (EVs) obtained from 42 patients and 17 healthy controls and analyzed the data with respect to the stage of the disease, patient survival, response to azacitidine, mutational status, and RNA editing. Significantly higher amounts of RNA material and a striking imbalance in RNA content between plasma and EVs (more than 400 significantly deregulated sncRNAs) were found in MDS patients compared to healthy controls. Moreover, the RNA content of EV cargo was more homogeneous than that of total plasma, and different RNAs were deregulated in these two types of material. Differential expression analyses identified that many hematopoiesis-related miRNAs (e.g., miR-34a, miR-125a, and miR-150) were significantly increased in MDS and that miRNAs clustered on 14q32 were specifically increased in early MDS. Only low numbers of circulating sncRNAs were significantly associated with somatic mutations in the SF3B1 or DNMT3A genes. Survival analysis defined a signature of four sncRNAs (miR-1237-3p, U33, hsa_piR_019420, and miR-548av-5p measured in EVs) as the most significantly associated with overall survival (HR = 5.866, p < 0.001). In total plasma, we identified five circulating miRNAs (miR-423-5p, miR-126-3p, miR-151a-3p, miR-125a-5p, and miR-199a-3p) whose combined expression levels could predict the response to azacitidine treatment. In conclusion, our data demonstrate that circulating sncRNAs show specific patterns in MDS and that their expression changes during disease progression, providing a rationale for the potential clinical usefulness of circulating sncRNAs in MDS prognosis. However, monitoring sncRNA levels in total plasma or in the EV fraction does not reflect one another, instead, they seem to represent distinctive snapshots of the disease and the data should be interpreted circumspectly with respect to the type of material analyzed.

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Tissue and exosomal miRNA editing in Non-Small Cell Lung Cancer

Cited by 41 publications

References 42 publications

Comprehensive Characterization of RNA Editing in Primary Gastric Adenocarcinoma through RNA-seq Data Analysis

Comprehensive Characterization of RNA Editing in Primary Gastric Adenocarcinoma through RNA-seq Data Analysis

Altered Biogenesis and MicroRNA Content of Hippocampal Exosomes Following Experimental Status Epilepticus

Circulating Small Noncoding RNAs Have Specific Expression Patterns in Plasma and Extracellular Vesicles in Myelodysplastic Syndromes and Are Predictive of Patient Outcome

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