The role of circulating exosomal microRNAs (miRNAs) in colorectal cancer (CRC) has drawn more and more attention during the past few years. Previously, we have identified several specific miRNAs in ...serum exosomes as potential CRC biomarkers. However, little is known about the association between exosome‐encapsulated miR‐548c‐5p and outcomes of patients with CRC. In the current study, the expression of serum exosomal miR‐548c‐5p was investigated by quantitative real‐time polymerase chain reaction. Its correlation with CRC prognosis was estimated by Kaplan‐Meier survival and log‐rank tests. Cox regression analysis based on uni‐ and multivariate analyses was performed to estimate the relationship of exosome‐encapsulated miR‐548c‐5p with the clinicopathological factors of patients with CRC. Reduced levels of serum exosomal miR‐548c‐5p were more significant in CRC patients with liver metastasis and at later TNM stage (III/IV tumor stages). Serum exosomal miR‐548c‐5p could inhibit the proliferation of CRC cells, while the precise molecular mechanisms warranted further elucidation. In addition, decreased levels of serum exosomal miR‐548c‐5p were independently associated with shorter overall survival in CRC adjusted by age, sex, tumor grade vascular infiltration, TNM stage (III/IV tumor stages) and metastasis (hazard ratio = 3.40, 95% confidence interval 1.02‐11.27; P = 0.046). The downregulation of exosomal miR‐548c‐5p in serum predicts poor prognosis in patients with CRC. Exosomal miR‐548c‐5p may be a critical biomarker for CRC diagnosis and prognosis.
Our study first suggests that the downregulation of exosome‐delivered miR‐548c‐5p in serum predicts poor prognosis in patients with CRC. In addition to a candidate as the prognostic factor, serum exosomal miR‐548c‐5p may also be an important biomarker for CRC diagnosis. This study highlights the role of serum exosome‐encapsulated miR‐548c‐5p as a novel predictive biomarker and a promising drug target in CRC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
RNA interference (RNAi) is being extensively investigated as a potential therapeutic strategy for cancer treatment. However, RNAi-based therapeutics have not yet been used to treat cancer because of ...their instability and the difficulty of microRNA (miRNA) delivery. Plasmonic nanoparticle-based RNAi nanotherapeutics have been developed for accurate and sensitive diagnosis and a strong therapeutic effect on cancers by leveraging their ease-of-use and specific properties such as photothermal conversion. In this review, recent strategies and advances in plasmonic nanoparticle-based miRNA delivery are briefly presented to facilitate the detection and treatment of several cancers. The challenges and potential opportunities afforded by the RNAi-based theragnosis field are discussed. We expect that the RNAi-integrated plasmonic nanotherapeutics discussed in this review can provide insights for the early diagnosis and effective treatment of cancer.
RNA interference (RNAi) is a potential strategy for cancer diagnosis and treatment. Especially, plasmonic nanomaterial-based RNAi delivery systems have various advantages using its plasmonic property, such as optical imaging and photothermal effect. In this review, recently announced microRNA detection using plasmonic nanomaterials and small interfering RNA (siRNA)-based treatment techniques are briefly described for cancer therapy. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pseudogenes, abundant in the human genome, are traditionally considered as non-functional "junk genes." However, recent studies have revealed that pseudogenes act as key regulators at DNA, RNA or ...protein level in diverse human disorders (including cancer), among which pseudogene-derived long non-coding RNA (lncRNA) transcripts are extensively investigated and has been reported to be frequently dysregulated in various types of human cancer. Growing evidence demonstrates that pseudogene-derived lncRNAs play important roles in cancer initiation and progression by serving as competing endogenous RNAs (ceRNAs) through competitively binding to shared microRNAs (miRNAs), thus affecting both their cognate genes and unrelated genes. Herein, we retrospect those current findings about expression, functions and potential ceRNA mechanisms of pseudogene-derived lncRNAs in human cancer, which may provide us with some crucial clues in developing potential targets for cancer therapy in the future.
MicroRNAs (miRNAs) are important regulators of cell-autonomous gene expression that influence many biological processes. They are also released from cells and are present in virtually all body ...fluids, including blood, urine, saliva, sweat, and milk. The functional role of nutritionally obtained extracellular miRNAs is controversial, and irrefutable demonstration of exogenous miRNA uptake by cells and canonical miRNA function is still lacking. Here we show that miRNAs are present at high levels in the milk of lactating mice. To investigate intestinal uptake of miRNAs in newborn mice, we employed genetic models in which newborn miR-375 and miR-200c/141 knockout mice received milk from wild-type foster mothers. Analysis of the intestinal epithelium, blood, liver, and spleen revealed no evidence for miRNA uptake. miR-375 levels in hepatocytes were at the limit of detection and remained orders of magnitude below the threshold for target gene regulation (between 1000 and 10,000 copies/cell). Furthermore, our study revealed rapid degradation of milk miRNAs in intestinal fluid. Together, our results indicate a nutritional rather than gene-regulatory role of miRNAs in the milk of newborn mice.
Background: It is unclear whether maternal milk microRNAs are taken up by offspring.
Results: Milk microRNAs are not taken up into murine offspring tissues or blood but are degraded by the digestive system.
Conclusion: It is unlikely that milk microRNAs function through canonical microRNA silencing.
Significance: Nutritionally derived microRNAs are unlikely to cross the intestinal barrier and influence gene expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MALAT1, a highly conserved long noncoding RNA, is deregulated in several types of cancers. However, its role in esophageal squamous cell carcinoma (ESCC) and its posttranscriptional regulation remain ...poorly understood. In this study we provide first evidences that a posttranscriptional regulation mechanism of MALAT1 by miR-101 and miR-217 exists in ESCC cells. This posttranscriptional silencing of MALAT1 could significantly suppress the proliferation of ESCC cells through the arrest of G2/M cell cycle, which may be due to MALAT1-mediated up-regulation of p21 and p27 expression and the inhibition of B-MYB expression. Moreover, we also found the abilities of migration and invasion of ESCC cells were inhibited after overexpression of miR-101, miR-217, or MALAT1 siRNA. This might be attributed to the deregulation of downstream genes of MALAT1, such as MIA2, HNF4G, ROBO1, CCT4, and CTHRC1. A significant negative correlation exists between miR-101 or miR-217 and MALAT1 in 42 pairs of ESCC tissue samples and adjacent normal tissues. Mice xenograft data also support the tumor suppressor role of both miRNAs in ESCCs.
Background: MALAT1, a highly conserved long non-coding RNA (lncRNA), acts as oncogene in multiple human cancers.
Results: miR-101 and miR-217 can silence MALAT1 expression and then inhibit esophageal cancer proliferation, migration and invasion.
Conclusion: Tumor suppressor miR-101 and miR-217 can negatively regulate MALAT1 expression.
Significance: These data provide a new mechanism for MALAT1 regulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Couch's spadefoot toad (Scaphiopus couchii) spends most of the year underground in a hypometabolic state known as estivation. During this time, they overcome significant dehydration and lack of food ...through many mechanisms including employing metabolic rate depression (MRD), increasing urea concentration, switching to lipid oxidation as the primary energy source, and decreasing their breathing and heart rate. MicroRNA (miRNA) are known to regulate translation by targeting messenger RNA (mRNA) for degradation or temporary storage, with several studies having reported that miRNA is differentially expressed during MRD, including estivation. Thus, we hypothesized that miRNA would be involved in gene regulation during estivation in S. couchii heart. Next-generation sequencing and bioinformatic analyses were used to assess changes in miRNA expression in response to two-month estivation and to predict the downstream effects of this expression. KEGG and GO analyses indicated that ribosome and cardiac muscle contraction are among the pathways predicted to be upregulated, whereas cell signaling and fatty acid metabolism were predicted to be downregulated. Together these results suggest that miRNAs contribute to the regulation of gene expression related to cardiac muscle physiology and energy metabolism during estivation.
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•Spadefoot toads undergo estivation for ∼10 months in response to drought conditions.•4 miRNAs increase and 11 miRNAs decrease in S. couchii heart during estivation.•miRNAs predict upregulation of ribosome and cardiac muscle contraction.•miRNAs predict downregulation of cell signaling and fatty acid metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Breast cancer is one of the most prevalent cancers in women. Triple‐negative breast cancer consists 15% to 20% of breast cancer cases and has a poor prognosis. Cancerous transformation has several ...causes one of which is dysregulation of microRNAs (miRNAs) expression. Exosomes can transfer miRNAs to neighboring and distant cells. Thus, exosomal miRNAs can transfer cancerous phenotype to distant cells. We used gene expression omnibus (GEO) datasets and miRNA target prediction tools to find overexpressed miRNA in breast cancer cells and their target genes, respectively. Exosomes were extracted from MDA‐MB‐231 and MCF‐7 cells and characterized. Overexpression of the miRNAs of MDA‐MB‐231 cells and their exosomes were analyzed using quantitative Real‐time PCR. The target genes expression was also evaluated in the cell lines. Luciferase assay was performed to confirm the miRNAs: mRNAs interactions. Finally, MCF‐7 cells were treated with MDA‐MB‐231 cells’ exosomes. The target genes expression was evaluated in the recipient cells. GSE60714 results indicated that miR‐9 and miR‐155 were among the overexpressed miRNAs in highly metastatic triple negative breast cancer cells and their exosomes. Bioinformatic studies showed that these two miRNAs target PTEN and
DUSP14 tumor suppressor genes. Quantitative Real‐time PCR confirmed the overexpression of the miRNAs and downregulation of their targets. Luciferase assay confirmed that the miRNAs target
PTEN and
DUSP14. Treatment of MCF‐7 cells with MDA‐MB‐231 cells’ exosomes resulted in target genes downregulation in MCF‐7 cells. We found that miR‐9 and miR‐155 were enriched in metastatic breast cancer exosomes. Therefore, exosomal miRNAs can transfer from cancer cells to other cells and can suppress their target genes in the recipient cells.
Exosomes can transfer microRNAs (miRNAs) to neighboring and distant cells. Thus, exosomal miRNAs can transfer cancerous phenotype to distant cells. Exosomes were extracted from MDA‐MB‐231 and MCF‐7 cells and characterized. Overexpression of miR‐9 and miR‐155 of MDA‐MB‐231 cells and their exosomes were analyzed using quantitative Real‐time PCR (RT‐qPCR). Luciferase assay confirmed that the miRNAs target PTEN and DUSP14. Treatment of MCF‐7 cells with MDA‐MB‐231 cells’ exosomes resulted in target genes downregulation in MCF‐7 cells.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
ABSTRACT
The repair of a fractured bone is critical to the well‐being of humans. Failure of the repair process to proceed normally can lead to complicated fractures, exemplified by either a delay in ...union or a complete nonunion. Both of these conditions lead to pain, the possibility of additional surgery, and impairment of life quality. Additionally, work productivity decreases, income is reduced, and treatment costs increase, resulting in financial hardship. Thus, developing effective treatments for these difficult fractures or even accelerating the normal physiological repair process is warranted. Accumulating evidence shows that microRNAs (miRNAs), small noncoding RNAs, can serve as key regulatory molecules of fracture repair. In this review, a brief description of the fracture repair process and miRNA biogenesis is presented, as well as a summary of our current knowledge of the involvement of miRNAs in physiological fracture repair, osteoporotic fractures, and bone defect healing. Further, miRNA polymorphisms associated with fractures, miRNA presence in exosomes, and miRNAs as potential therapeutic orthobiologics are also discussed. This is a timely review as several miRNA‐based therapeutics have recently entered clinical trials for nonskeletal applications and thus it is incumbent upon bone researchers to explore whether miRNAs can become the next class of orthobiologics for the treatment of skeletal fractures.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult ...mammalian heart, the neonatal heart has an intrinsic regenerative capacity. Consequently, we hypothesized that birth imposes fundamental changes in cardiac fibroblasts which limit their regenerative capabilities. In support, we found that reprogramming efficacy in vitro was markedly lower with fibroblasts derived from adult mice versus those derived from neonatal mice. Notably, fibroblasts derived from adult mice expressed significantly higher levels of pro-angiogenic genes. Moreover, under conditions that promote angiogenesis, only fibroblasts derived from adult mice differentiated into tube-like structures. Targeted knockdown screening studies suggested a possible role for the transcription factor Epas1. Epas1 expression was higher in fibroblasts derived from adult mice, and Epas1 knockdown improved reprogramming efficacy in cultured adult cardiac fibroblasts. Promoter activity assays indicated that Epas1 functions as both a transcription repressor and an activator, inhibiting cardiomyocyte genes while activating angiogenic genes. Finally, the addition of an Epas1 targeting siRNA to the reprogramming cocktail markedly improved reprogramming efficacy in vivo with both the number of reprogramming events and cardiac function being markedly improved. Collectively, our results highlight differences between neonatal and adult cardiac fibroblasts and the dual transcriptional activities of Epas1 related to reprogramming efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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RNA interference (RNAi) based therapeutics are considered an endogenous mechanism for modulating gene expression. In addition, microRNAs (miRNAs) may be tractable targets for the ...treatment of Chronic Obstructive Pulmonary Disease (COPD). In this study miR146a was adsorbed onto poly (glycerol adipate-co-ω-pentadecalactone), PGA-co-PDL, nanoparticles (NPs) to reduce target gene IRAK1 expression. NPs were prepared using an oil-in-water single emulsion solvent evaporation method incorporating cationic lipid dioleoyltrimethylammoniumpropane (DOTAP). This resulted in NPs of 244.80 ± 4.40 nm at 15% DOTAP concentration, zeta potential (ZP) of +14.8 ± 0.26 mV and miR-146a (40 µg/ml) maximum adsorption onto 15% DOTAP NPs was 36.25 ± 0.35 µg per 10 mg NP following 24 h incubation. Using the MTT assay, it was observed that over 75% at 0.312 mg/ml of A549 cells remained viable after 18 h exposure to cationic NPs at a concentration of 1.25 mg/ml. Furthermore, the in vitro release profile of miR-146a from loaded NPs showed a continuous release up to 77% after 24 h. Internalization of miR-146a loaded cationic NPs was observed in A549 cell lines using fluorescence and confocal microscopy. The miR146a delivered as miR-146a-NPs had a dose dependent effect of highest NPs concentrations 0.321 and 0.625 mg/ml and reduced target gene IRAK1 expression to 40%. In addition, IL-8 promoter reporter output (GFP) was dampened by miR-146a-NPs. In conclusion, miR-146a was successfully adsorbed onto PGA-co-PDL-DOTAP NPs and the miR-146a retained biological activity. Therefore, these results demonstrate the potential of PGA-co-PDL NPs as a delivery system for miR-146a to treat COPD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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