Hsa-miR-483-5p/mRNA network that regulates chemotherapy resistance in locally advanced rectal cancer identified through plasma exosome transcriptomics

BACKGROUND Chemoresistance is the primary contributor to distant metastasis in the context of neoadjuvant chemoradiotherapy(nCRT)for rectal cancer.However,the underlying mechanisms remain elusive.AIM To detect the differential expression profiles of plasma exosomal microRNAs(miRNAs)in poor and good responders and explore the potential mechanisms of chemoresistance.METHODS In this study,the profiles of plasma exosomal miRNAs were compared in two dimensions according to treatment responses(poor/good responders)and treatment courses(pre/post-nCRT)using RNA sequencing.RESULTS Exosome hsa-miR-483-5p was up-regulated in good responders post-nCRT.Bioinformatics analysis revealed that the target genes of hsa-miR-483-5p were mainly enriched in tumor-specific pathways,such as the MAPK signaling pathway,EGFR tyrosine kinase inhibitor resistance,Toll-like receptor signaling pathway,VEGF signaling pathway,and mTOR signaling pathway.Further analysis indicated that MAPK3,RAX2,and RNF165 were associated with inferior recurrence-free survival in patients with rectal cancer,and the profiles of MAPK3,TSPYL5,and ZNF-417 were correlated with tumor stage.In addition,the expression profiles of MAPK3,RNF165,and ZNF417 were negatively correlated with inhibitory concentration 50 values.Accordingly,an hsa-miR-483-5p/MAPK3/RNF 165/ZNF417 network was constructed.CONCLUSION This study provides insights into the mechanism of chemoresistance in terms of exosomal miRNAs.However,further research is required within the framework of our established miRNA-mRNA network.

Exosomal miRNA in early-stage hepatocellular carcinoma

The incidence and mortality of hepatic carcinoma(HCC)remain high,and early diagnosis of HCC is seen as a key approach in improving clinical outcomes.However,the sensitivity and specificity of current early screening methods for HCC are not satisfactory.In recent years,research around exosomal miRNA has gradually increased,and these molecules have emerged as attractive candidates for early diagnosis and treatment of HCC.This review summarizes the feasibility of using miRNAs in peripheral blood exosomes as early diagnostic tools for HCC.

Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage

Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage(ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase Ⅶ into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10(PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3(NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.

Comprehensive analysis of miRNA-gene regulatory network with clinical significance in human cancers

microRNAs(miRNAs),particularly the exosomal miRNAs have been widely used as biomarkers and promising therapeutic targets in cancer.However,a comprehensive analysis of miRNA-gene regulatory network with clinical significance remains scarce.The emergence of high-throughput multi-omics data over large,well-characterized patient cohorts provides an unprecedented opportunity to address this problem.Herein,we performed a clinic-centered analysis to identify cancer-associated miRNAs,miRNA-target axis.We first calculated the correlation among miRNA,mRNA and 75 unique clinico-pathological characteristics(CPCs)in 26 cancer types,and established an online resource(4CR).Interestingly,we found that the high expression of several DNA methylation-related enzymes was associated with adverse outcomes of cancer patients,and these genes were regulated by a cluster of miRNAs.Furthermore,by integrating exosomal miRNA and m RNA databases,we identified exosomal miRNA biomarkers for non-invasive cancer surveillance and therapy monitoring.Finally,we explored the role of CPC-related miRNAs for therapeutic effect prediction of drugs based on their shared targets.Our analysis pipeline illustrated the significance of clinic-centered analysis in miRNA-gene pair identification and provided helpful clues for future cancer studies.

Peripheral origin exosomal micro RNAs aggravate glymphatic system dysfunction in diabetic cognitive impairment

Cognitive dysfunction is one of the common central nervous systems(CNS)complications of diabetes mellitus,which seriously affects the quality of life of patients and results in a huge economic burden.The glymphatic system dysfunction mediated by aquaporin-4(AQP4)loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment(DCI).However,the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear.Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators.Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus,and skeletal muscle,liver and adipose tissue are the key target insulin resistance organs.In this review,the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed.We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet,which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI.Furthermore,the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized,which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.

The role of exosomal microRNAs;focus on clinical applications in breast cancer

Despite several advances in targeted therapies for breast cancer,breast-cancer-associated death remains high in women.This is partially due to the lack of reliable markers predicting metastatic disease or recurrence after initial therapy.Recent research into the clinical validity of circulating cancer-specific biomarkers as a“liquid biopsy”is of growing interest.Of these,exosomal microRNAs(miRNAs)are promising candidate biomarkers for clinical use in breast cancer.In addition to their diagnostic value,exosomal miRNAs play an important role in predicting clinical outcome or treatment response.In this review,it is focused on the findings concerning exosomal miRNAs in relation to disease detection,prognostic impact and therapeutic effect in breast cancer,and discuss their clinical utility.

An electrochemical biosensor based on DNA“nano-bridge”for amplified detection of exosomal microRNAs

Exosomal miRNAs,as potential biomarkers in liquid biopsy for cancer early diagnosis,have aroused widespread concern.Herein,an electrochemical biosensor based on DNA“nano-bridge”was designed and applied to detect exosomal microRNA-21(miR-21)derived from breast cancer cells.In brief,the target miR-21 can specifically open the hairpin probe 1(HP1)labeled on the gold electrode(GE)surface through strand displacement reaction.Thus the exposed loop region of HP1 can act as an initiator sequence to activate the hybridization chain reaction(HCR)between two kinetically trapped hairpin probes:HP2 immobilized on the GE surface and biotin labeled HP3 in solution.Cascade HCR leads to the formation of DNA“nano-bridge”tethered to the GE surface with a great deal of“piers”.Upon addition of avidin-modified horseradish peroxidase(HRP),numerous HRP were bound to the formed“nano-bridge”through biotin-avidin interaction to arouse tremendous current signal.In theory,only a single miR-21 is able to trigger the continuous HCR between HP2 and HP3 until all of the HP2 are exhausted.Therefore the proposed biosensor achieved ultrahigh sensitivity toward miR-21 with the detection limit down to 168 amol/L,as well as little cross-hybridization even at the single-base-mismatched level.Successful attempts were also made in the detection of exosomal miR-21 obtained from the MCF-7 of breast cancer cell line.To our knowledge,this is the first attempt to built horizontal DNA nano-structure on the electrode surface for exosomal miRNAs detection.In a word,the high sensitivity,selectivity,low cost make the proposed method hold great potential application for early point-of-care(POC)diagnostics of cancer.

Research on the therapeutic prospect of exosomal miR-122-5p and miR-206 in treatment of chronic heart failure

Background Exosomes are bilayer lipid membranous vesicles with a diameter of 40-100 nm.They play an important role in signal transduction among cellular substances.Exosomes miR-206 and miR-122-5 have been found to play a regulatory role in cardiovascular diseases such as chronic heart failure,and therefore have gradually become the focus of various studies.The review has introduced the biological characteristics of the exosomal microRNAs,the association between exosomes miR-122-5 p,miR-206 and chronic heart failure,and briefly described the therapeutic prospects of these two exosomal miRNAs in the treatment of chronic heart failure.It may provide some new directions for the diagnosis and treatment of heart failure.