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With the advancement of RNA sequencing technology, there has been a drive to uncover and elucidate the pivotal role of A-to-I RNA editing events in tumorigenesis. However, A-to-I miRNA editing events have been clearly identified in bladder cancer, the molecular mechanisms underlying their role in bladder cancer remain unclear. In our investigation, we observed a notable under-expression of edited miR-154-p13-5p in bladder cancer (BC) tissues, in contrast to normal counterparts. Remarkably, heightened expression levels of edited miR-154-p13-5p correlated with improved survival outcomes. To assess the impact of modified miR-154-p13-5p, we conducted a string of cell phenotype assays through transfection of the corresponding miRNAs or siRNAs. The results unequivocally demonstrate that edited miR-154-p13-5p exerts a substantial inhibitory influence on proliferation, migration, and induces apoptosis by specifically targeting LIX1L in bladder cancer. Moreover, we observed that the editing of miR-154-p13-5p or LIX1L-siRNAs inhibits the expression of LIX1L, thereby suppressing EMT-related proteins and cell cycle protein CDK2. Simultaneously, an upregulation in the expression levels of Caspase-3 and Cleaved Caspase-3 were also detected. Our research findings suggest that the upregulation of edited miR-154-p13-5p could potentially enhance the prognosis of bladder cancer, thereby presenting molecular biology-based therapeutic strategies.

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This study aimed to identify active miRNA editing sites during adipose development in Ningxiang pigs and analyze their characteristics and functions. Based on small RNA-seq data from the subcutaneous adipose tissues of Ningxiang pigs at four stages-30 days (piglet), 90 days (nursery), 150 days (early fattening), and 210 days (late fattening)-we constructed a developmental map of miRNA editing in the adipose tissues of Ningxiang pigs. A total of 505 miRNA editing sites were identified using the revised pipeline, with C-to-U editing types being the most prevalent, followed by U-to-C, A-to-G, and G-to-U. Importantly, these four types of miRNA editing exhibited base preferences. The number of editing sites showed obvious differences among age groups, with the highest occurrence of miRNA editing events observed at 90 days of age and the lowest at 150 days of age. A total of nine miRNA editing sites were identified in the miRNA seed region, with significant differences in editing levels (p < 0.05) located in ssc-miR-23a, ssc-miR-27a, ssc-miR-30b-5p, ssc-miR-15a, ssc-miR-497, ssc-miR-15b, and ssc-miR-425-5p, respectively. Target gene prediction and KEGG enrichment analyses indicated that the editing of miR-497 might potentially regulate fat deposition by inhibiting adipose synthesis via influencing target binding. These results provide new insights into the regulatory mechanism of pig fat deposition.

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MiRNAs are edited or modified in multiple ways during their biogenesis pathways. It was reported that miRNA editing was deregulated in tumors, suggesting the potential value of miRNA editing in cancer classification. Here we extracted three types of miRNA features from 395 LUAD and control samples, including the abundances of original miRNAs, the abundances of edited miRNAs, and the editing levels of miRNA editing sites. Our results show that eight classification algorithms selected generally had better performances on combined features than on the abundances of miRNAs or editing features of miRNAs alone. One feature selection algorithm, i.e., the DFL algorithm, selected only three features, i.e., the frequencies of hsa-miR-135b-5p, hsa-miR-210-3p and hsa-mir-182_48u (an edited miRNA), from 316 training samples. Seven classification algorithms achieved 100% accuracies on these three features for 79 independent testing samples. These results indicate that the additional information of miRNA editing is useful in improving the classification of LUAD samples.

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Leukemia is an aberrant hyper-proliferation of immature blood cells that do not form solid tumors. The transcriptomes of microRNAs (miRNAs) of leukemia have been intensively explored. However, miRNA editing of leukemia has not been extensively studied. To identify miRNA editing patterns and explore their functional relevance in leukemia, we analyzed 200 small RNA sequencing profiles of three subtypes of leukemia and identified hundreds of miRNA editing sites in three subtypes of leukemia. Then, we compared the editing levels of identified miRNA editing sites in leukemia and normal controls. Many miRNAs were differential edited in different subtypes of leukemia. We also found the editing levels of 3'-A editing sites of hsa-mir-21-5p and hsa-mir-155-5p decreased in chronic lymphocytic leukemia patients with radiation treatments. By integrating PAR-CLIP sequencing profiles, we predicted the targets of original and edited miRNAs. One of the edited miRNA, hsa-let-7b_5c, with an additional cytosine at 5' end of hsa-let-7b-5p, potentially targeted VBP1 and CTDSP1. CTDSP1 was significantly downregulated in T-ALL compared to normal controls, which might be originated from the hyperediting of hsa-let-7b-5p in T-ALL. Our study provides a comprehensive view of miRNA editing in three different subtypes of leukemia.

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Despite the development of targeted therapeutics, immunotherapy, and strategies for early detection, lung cancer carries a high mortality. Further, significant racial disparities in outcomes exist for which the molecular drivers have yet to be fully elucidated. The growing field of Epitranscriptomics has introduced a new layer of complexity to the molecular pathogenesis of cancer. RNA modifications can occur in coding and non-coding RNAs, such as miRNAs, possibly altering their gene regulatory function. The potential role for such modifications as clinically informative biomarkers remains largely unknown. Here, we concurrently profiled canonical miRNAs, shifted isomiRs (templated and non-templated), and miRNAs with single-point modification events (RNA and DNA) in White American (W) and Black or African American (B/AA) lung adenocarcinoma (LUAD) patients. We found that while most deregulated miRNA isoforms were similar in W and B/AA LUAD tissues compared to normal adjacent tissues, there was a subgroup of isoforms with deregulation according to race. We specifically investigated an edited miRNA, miR-151a-3p with an A-to-I editing event at position 3, to determine how its altered expression may be associated with activation of divergent biological pathways between W and B/AA LUAD patients. Finally, we identified distinct race-specific miRNA isoforms that correlated with prognosis for both Ws and B/AAs. Our results suggested that concurrently profiling canonical and non-canonical miRNAs may have potential as a strategy for identifying additional distinct biological pathways and biomarkers in lung cancer.

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder whose pathogenesis is still unclear. MicroRNAs (miRNAs) are a kind of endogenous small non-coding RNAs that play important roles in the post-transcriptional regulation of genes. Recent researches show that miRNAs are edited in multiple ways especially in central nervous systems. A-to-I editing of RNA catalyzed by Adenosine deaminases acting on RNA (ADARs) happens intensively in brain and is also noticed in other organs and tissues. Although miRNAs are widely edited in human brain, miRNA editing in ASD is still largely unexplored. In order to reveal the editing events of miRNAs in ASD, we analyzed 131 miRNA-seq samples from 8 different brain regions of ASD patients and normal controls. We identified 834 editing sites with significant editing levels, of which 70 sites showed significantly different editing levels in the superior frontal gyrus samples of ASD patients (ASD-SFG) when compared with those of control samples. The editing level of an A-to-I editing site in hsa-mir-376a-1 (hsa-mir-376a-1_9_A_g) in ASD-SFG is higher than that of normal controls, and the difference is exaggerated in individuals under 10 years. The increased expression of ADAR1 is consistent with the increased editing level of hsa-mir-376a-1_9_A_g in ASD-SFG samples compared to normal SFG samples. Furthermore, we verify that A-to-I edited hsa-mir-376a-5p directly represses GPR85 and NAPB, which may contribute to the abnormal neuronal development of ASD patients. These results provide new insights into the mechanism of ASD.

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Adipose dysfunction with aging increases risk to insulin resistance and other chronic metabolic diseases. We previously showed functional changes in microRNAs involved in pre-adipocyte differentiation with aging resulting in adipose dysfunction. However, the mechanisms leading to this dysfunction in microRNAs in adipose tissue (adipomiRs) during aging are not well understood. We determined the longitudinal changes in expression of adipomiRs and studied their regulatory mechanisms, such as miRNA biogenesis and editing, in an aging rodent model, with Fischer344 × Brown-Norway hybrid rats at ages ranging from 3 to 30 months (male/females, n > 8). Expression of adipomiRs and their edited forms were determined by small-RNA sequencing. RT-qPCR was used to measure the mRNA expression of biogenesis and editing enzymes. Sanger sequencing was used to validate editing with aging. Differential expression of adipomiRs involved in adipocyte differentiation and insulin signaling was altered with aging. Sex- and age-specific changes in edited adipomiRs were observed. An increase in miRNA biogenesis and editing enzymes (ADARs and their splice variants) were observed with increasing age, more so in female than male rats. The adipose dysfunction observed with age is attributed to differences in editing of adipomiRs, suggesting a novel regulatory pathway in aging.

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MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called "RNA editing" involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA's stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA's ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity.

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BACKGROUND: Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Small non-coding RNAs (sRNAs), particularly microRNAs (miRNAs), regulate several cellular processes and have an important role in many human malignancies including PCa. We assessed the sRNA profiles associated with PCa in Arabs, a population that has rarely been studied. METHODS: We used next generation sequencing technology to obtain the entire sRNA transcriptome of primary prostate tumor formalin-fixed paraffin-embedded tissues, and their paired non-tumor tissues, collected from Bedouin patients (Qatari and Saudi). The miRNA and the target gene expression were evaluated by real-time quantitative PCR. miRNA KEGG pathway and miRNA target genes were subsequently analyzed by starBase and TargetScan software. RESULTS: Different expression patterns of several sRNA and miRNA editing were revealed between PCa tumor and their paired non-tumor tissues. Our study identified four miRNAs that are strongly associated with prostate cancer, which have not been reported previously. Differentially expressed miRNAs significantly affect various biological pathways, such as cell cycle, endocytosis, adherence junction and pathways involved in cancer. Prediction of potential targets for the identified miRNAs indicates the overexpression of KRAS, BCL2 and down-regulation of PTEN in PCa tumor tissues. CONCLUSION: These miRNAs, newly associated with prostate cancer, may represent not only markers for the increased risk of PCa in Arabs, but may also reflect the clinical and pathological diversity as well as the ethno-specific heterogeneity of prostate cancer.

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MicroRNAs (miRNAs) play key regulatory roles in various biological processes and diseases. A comprehensive analysis of large scale small RNA sequencing data (smRNA-seq) will be very helpful to explore tissue or disease specific miRNA markers and uncover miRNA variants. Here, we systematically analyzed 410 human smRNA-seq datasets, which samples are from 24 tissue/disease/cell lines. We tested the mapping strategies and found that it was necessary to make multiple-round mappings with different mismatch parameters. miRNA expression profiles revealed that on average ∼70% of known miRNAs were expressed at low level or not expressed (RPM < 1) in a sample and only ∼9% of known miRNAs were relatively highly expressed (RPM > 100). About 30% known miRNAs were not expressed in all of our used samples. The miRNA expression profiles were compiled into an online database (HMED, http://bioinfo.life.hust.edu.cn/smallRNA/). Dozens of tissue/disease specific miRNAs, disease/control dysregulated miRNAs and miRNAs with arm switching events were discovered. Further, we identified some highly confident editing sites including 24 A-to-I sites and 23 C-to-U sites. About half of them were widespread miRNA editing sites in different tissues. We characterized that the 2 types of editing sites have different features with regard to location, editing level and frequency. Our analyses for expression profiles, specific miRNA markers, arm switching, and editing sites, may provide valuable information for further studies of miRNA function and biomarker finding.

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