Exosomal ncRNAs Research Articles

Cross-Talk between Mitochondrial Dysfunction-Provoked Oxidative Stress and Aberrant Noncoding RNA Expression in the Pathogenesis and Pathophysiology of SLE.

Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease involving almost every organ. Polygenic predisposition and complicated epigenetic regulations are the upstream factors to elicit its development. Mitochondrial dysfunction-provoked oxidative stress may also play a crucial role in it. Classical epigenetic regulations of gene expression may include DNA methylation/acetylation and histone modification. Recent investigations have revealed that intracellular and extracellular (exosomal) noncoding RNAs (ncRNAs), including microRNAs (miRs), and long noncoding RNAs (lncRNAs), are the key molecules for post-transcriptional regulation of messenger (m)RNA expression. Oxidative and nitrosative stresses originating from mitochondrial dysfunctions could become the pathological biosignatures for increased cell apoptosis/necrosis, nonhyperglycemic metabolic syndrome, multiple neoantigen formation, and immune dysregulation in patients with SLE. Recently, many authors noted that the cross-talk between oxidative stress and ncRNAs can trigger and perpetuate autoimmune reactions in patients with SLE. Intracellular interactions between miR and lncRNAs as well as extracellular exosomal ncRNA communication to and fro between remote cells/tissues via plasma or other body fluids also occur in the body. The urinary exosomal ncRNAs can now represent biosignatures for lupus nephritis. Herein, we’ll briefly review and discuss the cross-talk between excessive oxidative/nitrosative stress induced by mitochondrial dysfunction in tissues/cells and ncRNAs, as well as the prospect of antioxidant therapy in patients with SLE.

Biological functions and clinical applications of exosomal non-coding RNAs in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.

Circulating exosomal noncoding RNAs as prognostic biomarkers in human hepatocellular carcinoma.

Exosomal noncoding RNAs (ncRNAs) have unique expression profiles reflecting the characteristics of a tumor, and their role in tumor progression and metastasis is emerging. However, the significance of circulating exosomal ncRNAs in the prognosis of hepatocellular carcinoma (HCC) remains to be elucidated. We therefore determined the prognostic significance of circulating exosomal ncRNAs (miRNA-21 and lncRNA-ATB) for human HCC. This prospective study enrolled 79 HCC patients between October 2014 and September 2015. Exosomes were extracted from serum samples using the ExoQuick Exosome Precipitation Solution. To validate the isolation of the exosomes from serum, immunoblotting for exosome markers and characterization of nanoparticle using NanoSight were performed. NcRNAs were isolated from exosomes using the miRNeasy serum/plasma micro kit. Both circulating exosomal miRNA-21 and lncRNA-ATB were related to TNM stage and other prognostic factors, including the T stage and portal vein thrombosis. Multivariate analysis using the Cox regression test identified that both higher miRNA-21 and higher lncRNA-ATB were independent predictors of mortality and disease progression, along with larger tumor size and higher C-reactive protein (all p < 0.05). The overall survival and progression-free survival were significantly lower in patients with higher circulating levels of exosomal miRNA-21 (≥0.09) and lncRNA-ATB (≥0.0016) (log-rank test: p < 0.05). In conclusion, our study has provided strong evidence that circulating exosomal ncRNAs (miRNA-21 and lncRNA-ATB) are novel prognostic markers and therapeutic targets for HCC.

Selective loading of exosomal HULC and miR-372 is responsible for chondrocyte death during OA pathogenesis

ABSTRACTExosomes are membranous vesicles containing various biomolecules, including non-coding RNAs (ncRNAs). ncRNAs are secreted from several cell types and are involved in various biological functions, including cellular communication. The aim of this study was to identify and illustrate the significance of the osteoarthritis (OA)-specific packaging of exosomal ncRNAs. In this study, we hypothesized that selective packaging of ncRNAs into exosomes would reflect the cellular response to chondrocyte death during OA pathogenesis. Exosomal HULC level significantly decreased in OA exosomes, whereas exosomal miR-372-3p level significantly increased in OA exosomes. In addition, chondrocytes with high HULC levels in the cytosol showed lower overall proliferation and higher apoptotic cell death than normal chondrocytes, whereas chondrocytes with high miR-372-3p in the cytosol showed higher overall proliferation and lower cell death than OA chondrocytes. Among the signaling molecules known to be involved in OA pathogenesis, GSK is one of the regulators of the selective exosomal packaging observed in OA chondrocytes. Inhibition of GSK observed in OA chondrocytes was responsible for enriched uploading of miR-372-3p and suppressed uploading of HULC during OA pathogenesis. In conclusion, we show that selective ncRNAs observed in OA play a critical role in chondrocyte proliferation/apoptosis.

The emerging role of exosome-derived non-coding RNAs in cancer biology

Exosomes are a new means of intercellular information exchange that have aroused great research interest. Long neglected in research, exosomes were deemed nonfunctional cellular components to be discarded. However, it has been gradually revealed that exosomes are an important tool for the exchange of intercellular information and material. Exosomes contain specific repertoires of non-coding RNAs (ncRNAs, including microRNA and lncRNA), indicating that a specific RNA sorting mechanism may exist. Correspondingly, intracellular multivesicular bodies (MVBs) are produced after fusion with the cell membrane to release exosomes rather than inducing autophagy, which reveals that there may be a specific regulatory mechanism for MVB secretion. Cells can trigger cancer-related disorders after the recognition and uptake of circulating exosomal ncRNAs, providing indications for early tumor biopsy and treatment. The use of exosomes as a biological carrier in targeted therapy has been demonstrated. However, there may be a specific, unknown switch for loading drugs. This review focuses on the mechanisms of exosome biogenesis, release, and uptake. We also review the promotion of tumor development by exosomal ncRNAs including chemotherapy resistance, metastasis and the prospective use of exosomes in cancer diagnosis and treatment.

Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease.

In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRNAs, tRNA fragments (tRFs), mitochondrial tRNAs, or lincRNAs. For their computational identification from RNA-seq data, we developed a novel computational pipeline, designated as ncRNASeqScan. By these analyses, in CKD patients we identified 30 differentially expressed ncRNAs, derived from urinary exosomes, as suitable biomarkers for early diagnosis. Thereby, miRNA-181a appeared as the most robust and stable potential biomarker, being significantly decreased by about 200-fold in exosomes of CKD patients compared to healthy controls. Using a cell culture system for CKD indicated that urinary exosomes might indeed originate from renal proximal tubular epithelial cells.

Diagnostic relevance of circulating cell-free and exosomal microRNAs and long non-coding RNAs in blood of cancer patients

Abstract MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) belong to a large group of non-coding RNA (ncRNA) molecules that possess diverse functions in epigenetic and chromatin structure modifications. In particular, they post-transcriptionally inhibit the protein expression of their target mRNAs and therefore, are involved in different tumor-associated signaling pathways. As the expression of both ncRNAs is frequently dysregulated in cancer and shows unique signatures, they may play a crucial role in cancer pathogenesis. They are passively and actively released into the blood circulation, and accordingly, their plasma/serum and exosomal profiles reflect disease development, tumor load and malignant progression towards metastatic relapse. Considering the biology and nature of ncRNAs in the regulation of different cellular processes, they may have potential clinical utility as blood-based tumor markers and future therapeutic targets in the treatment of cancer patients. The present review focuses on the diagnostic value of cell-free and exosomal ncRNAs in plasma/serum of cancer patients and the challenges to establish them as future tumor markers.

Exosomal Non-Coding RNAs: Diagnostic, Prognostic and Therapeutic Applications in Cancer.

Non-coding RNAs, such as microRNAs and long non-coding RNAs, are important regulatory molecules which are corrupted in cancer, often in a tissue and stage specific manner. Accumulated data suggests that these promising biomarkers, may also form the basis of novel targeted therapeutic strategies. The role of exosomes in cancer development and metastasis pathways is also increasingly well described. These endosome derived extracellular vesicles which are trafficked horizontally between tumor cells, and vertically between tumor cells and the surrounding microenvironment, carry bioactive cargos, which can reprogram the phenotype of recipient cells with important oncogenic consequences.Exosomes are enriched with non-coding RNA content. Within exosomes, non-coding RNAs are secreted into the peripheral circulation and other bodily fluids where they are protected from enzymatic degradation by the surrounding phospholipid membrane. Exosomes are therefore a highly promising source of diagnostic and prognostic material in cancer. Furthermore, as exosomes are natural ncRNA carriers, they may be adapted for the purpose of drug delivery by the introduction of exogenous ncRNAs or by manipulating their endogenous ncRNA content. In the current review, we will explore these highly clinically relevant themes by examining the roles of exosomal ncRNAs in cancer diagnostics, prognostics and therapy.