Dysregulation of microRNAs (miRNAs) is involved in the initiation and progression of several human cancers, including breast cancer (BC), as strong evidence has been found that miRNAs can act as ...oncogenes or tumor suppressor genes. This review presents the state of the art on the role of miRNAs in the diagnosis, prognosis, and therapy of BC. Based on the results obtained in the last decade, some miRNAs are emerging as biomarkers of BC for diagnosis (i.e., miR-9, miR-10b, and miR-17-5p), prognosis (i.e., miR-148a and miR-335), and prediction of therapeutic outcomes (i.e., miR-30c, miR-187, and miR-339-5p) and have important roles in the control of BC hallmark functions such as invasion, metastasis, proliferation, resting death, apoptosis, and genomic instability. Other miRNAs are of interest as new, easily accessible, affordable, non-invasive tools for the personalized management of patients with BC because they are circulating in body fluids (e.g., miR-155 and miR-210). In particular, circulating multiple miRNA profiles are showing better diagnostic and prognostic performance as well as better sensitivity than individual miRNAs in BC. New miRNA-based drugs are also promising therapy for BC (e.g., miR-9, miR-21, miR34a, miR145, and miR150), and other miRNAs are showing a fundamental role in modulation of the response to other non-miRNA treatments, being able to increase their efficacy (e.g., miR-21, miR34a, miR195, miR200c, and miR203 in combination with chemotherapy).
Obesity paradox (OP) describes a widely observed clinical finding of improved cardiovascular fitness and survival in some overweight or obese patients. The molecular mechanisms underlying OP remain ...enigmatic partly due to a lack of animal models mirroring OP in patients. Using apolipoprotein E knock-out (apoE−/−) mice on a high fat (HF) diet as an atherosclerotic obesity model, we demonstrated 1) microRNA-155 (miRNA-155, miR-155) is significantly up-regulated in the aortas of apoE−/− mice, and miR-155 deficiency in apoE−/− mice inhibits atherosclerosis; 2) apoE−/−/miR-155−/− (double knock-out (DKO)) mice show HF diet-induced obesity, adipocyte hypertrophy, and present with non-alcoholic fatty liver disease; 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin and increased expression of adipogenic transcription factors but lack glucose intolerance and insulin resistance. Our results are the first to present an OP model using DKO mice with features of decreased atherosclerosis, increased obesity, and non-alcoholic fatty liver disease. Our findings suggest the mechanistic role of reduced miR-155 expression in OP and present a new OP working model based on a single miRNA deficiency in diet-induced obese atherogenic mice. Furthermore, our results serve as a breakthrough in understanding the potential mechanism underlying OP and provide a new biomarker and novel therapeutic target for OP-related metabolic diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MicroRNAs (miRNAs) are short non-coding RNAs that act as important regulators of gene expression as part of the epigenetic machinery. In addition to posttranscriptional gene silencing by miRNAs, the ...epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of complex diseases, such as late onset and fluctuation of symptoms. However, miRNAs not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenome and miRNome, and any dysregulation of this complex system can result in various physiological and pathological conditions. In addition, miRNAs play an important role in toxicogenomics and may explain the relationship between toxicant exposure and tumorigenesis. The present review provides information on 63 miRNA genes shown to be epigenetically regulated in association with 21 diseases, including 11 cancer types: cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung’s disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, pulmonary fibrosis, melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal, gastric, cervical, ovarian, prostate, lung, breast, and bladder cancer. The review revealed that hsa-miR-34a, hsa-miR-34b, and hsa-miR-34c are the most frequently reported epigenetically dysregulated miRNAs. There is a need to further study molecular mechanisms of various diseases to better understand the crosstalk between epigenetics and gene expression and to develop new therapeutic options and biomarkers.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Adenosine deaminases acting on RNA-1 (ADAR1) involves adenosine to inosine RNA editing and microRNA processing. ADAR1 is known to be involved in the replication of various viruses, including ...hepatitis C and D. However, the role of ADAR1 in hepatitis B virus (HBV) infection has not yet been elucidated. Here, for the first time, we demonstrated ADAR1 antiviral activity against HBV. ADAR1 has two splicing isoforms in human hepatocytes: constitutive p110 protein and interferon-α (IFN-α)-responsive p150 protein. We found that overexpression of ADAR1 decreased HBV RNA in an HBV culture model. A catalytic-site mutant ADAR1 also decreased HBV RNA levels, whereas another adenosine deaminases that act on the RNA (ADAR) family protein, ADAR2, did not. Moreover, the induction of ADAR1 by stimulation with IFN-α also reduced HBV RNA levels. Decreases in endogenous ADAR1 expression by knock-down or knock-out increased HBV RNA levels. A major hepatocyte-specific microRNA, miRNA-122, was found to be positively correlated with ADAR1 expression, and exogenous miRNA-122 decreased both HBV RNA and DNA, whereas, conversely, transfection with a miRNA-122 inhibitor increased them. The reduction of HBV RNA by ADAR1 expression was abrogated by p53 knock-down, suggesting the involvement of p53 in the ADAR1-mediated reduction of HBV RNA. This study demonstrated, for the first time, that ADAR1 plays an antiviral role against HBV infection by increasing the level of miRNA-122 in hepatocytes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MicroRNAs (miRNAs, miR) are of critical importance in growth and metastasis of cancer cells; however, the underlying functions of miRNAs in osteosarcoma (OS) remain largely unknown. This study was ...aimed to elucidate the role of miR‐221 in regulating the biological behavior of OS cells. The proliferation ability was examined by cell counting kit‐8 (CCK‐8) and cell cycle assay. The abilities of cell migration, invasion, and apoptosis were monitored by transwell assay and flow cytometry, respectively. The effect of miR‐221 on cyclin‐dependent kinase inhibitor 1B (CDKN1B) expression was evaluated by luciferase assays, real‐time polymerase chain reaction, and Western blot analysis. We found that miR‐221 was elevated in OS cell lines compared with the normal osteoblastic cell line. Transfection of the miR‐221 inhibitor into MG63 and U‐2OS cell lines obviously suppressed cell proliferation, migration, and invasion, which is accompanied with cell cycle arrest in G0/G1 phase. Furthermore, luciferase reporter assays indicated that CDKN1B is directly targeted by miR‐221 in OS cells. Knockdown of CDKN1B inhibited the effects of miR‐221 inhibitor, along with decreased Bax and caspase‐3 and increased cyclin E, cyclin D1, Bcl‐2, Snail, and Twist1 expression. The results suggested that miR‐221 might act as a potentially useful target for treatment of OS.
Transfection of microRNA (miR)‐221 inhibitor into osteosarcoma (OS) cell lines obviously suppressed cell proliferation, migration, and invasion, which is accompanied with cell cycle arrest in the G0/G1 phase. CDKN1B is directly targeted by miR‐221. Knockdown of CDKN1B inhibited the effects of miR‐221 inhibitor, along with decreased Bax and caspase‐3 and increased cyclin E, cyclin D1, Bcl‐2, Snail, and Twist1 expression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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Roles of microRNAs in preeclampsia Lv, Yan; Lu, Cheng; Ji, Xiaohong ...
Journal of cellular physiology,
February 2019, Volume:
234, Issue:
2
Journal Article
Peer reviewed
Preeclampsia (PE) is a complex disorder that is characterized by hypertension and proteinuria after the 20th week of pregnancy, and it causes most neonatal morbidity and perinatal mortality. Most ...studies suggest that placental dysfunction is the main cause of PE. However, genetic factors, immune factors, and systemic inflammation are also related to the pathophysiology of this syndrome. Thus far, the exact pathogenesis of PE is not yet fully understood, and intense research efforts are focused on PE to elucidate the pathophysiological mechanisms. MicroRNAs (miRNAs) refer to small single‐stranded and noncoding molecules that can negatively regulate gene expression, and miRNA regulatory networks play an important role in diverse pathological processes. Many studies have confirmed deregulated miRNA in pregnant patients with PE, and the function and mechanism of these differentially expressed miRNA are gradually being revealed. In this review, we summarize the current research about miRNA involved in PE, including placenta‐specific miRNA, their predictive value, and their function in the development of PE. This review will provide fundamental evidence of miRNA in PE, and further studies are necessary to explore the roles of miRNA in the early diagnosis and treatment of PE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Decreased monocytic HLA-DR expression is the most studied biomarker of immune competency in critically ill and autoimmune disease patients. However, the underlying regulatory mechanisms remain ...largely unknown. One probable HLA-DR dysregulation is through microRNAs. The aim of this study was to investigate the effects of specific microRNAs on HLA-DR expression in human monocytic cells. Four up- and four down-HLA-DR-regulating microRNAs were identified, with hsa-miR-let-7f-2-3p showing the most significant upregulation and hsa-miR-567 and hsa-miR-3972 downregulation. Anti-inflammatory glucocorticoid medication Dexamethasone-decreased HLA-DR was significantly restored by hsa-miR-let-7f-2-3p and hsa-miR-5693. Contrarily, proinflammatory cytokines IFN-γ and TNF-α-increased HLA-DR were significantly reversed by hsa-miR-567. Clinically, paired plasma samples from patients before and one day after cardiac surgery revealed up-regulated expression of hsa-miR-5693, hsa-miR-567, and hsa-miR-3972, following the major surgical trauma. In silico approaches were applied for functional microRNA-mRNA interaction prediction and candidate target genes were confirmed by qPCR analysis. In conclusion, novel monocytic HLA-DR microRNA modulators were identified and validated in vitro. Moreover, both the interaction between the microRNAs and anti- and proinflammatory molecules and the up-regulated microRNAs identified in cardiac surgery highlight the potential clinical relevance of our findings.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
ptc-miR472a-overexpressing poplar exhibited resistance to Cytospora chrysosperma and susceptibility to Colletotrichum gloeosporioides, while silenced lines exhibited the opposite phenotype, ...identifying a new strategy to improve plant disease resistance.
Abstract
The hemibiotroph Colletotrichum gloeosporioides and the necrotroph Cytospora chrysosperma cause poplar foliage and stem disease, respectively, resulting in substantial economic losses. In this study, Populus trichocarpa ptc-miR472a was down-regulated in leaves treated with salicylic acid, jasmonic acid (JA) or bacterial flagellin (flg22). Here, ptc-miR472a and a short tandem target mimic (STTM) of miR472a were overexpressed in P. alba × P. glandulosa, and overexpression lines of miR472a and silenced lines of STTM472a were generated. Compared with the STTM472a and wild type lines, lower reactive oxygen species accumulation was detected in miR472a overexpressing plants treated with flg22, C. gloeosporioides or C. chrysosperma. In addition, the miR472a overexpressing lines exhibited the highest susceptibility to the hemibiotroph, C. gloeosporioides, but the highest effective defence response to the necrotroph, C. chrysosperma. The JA/ethylene marker gene ERF1 was rapidly up-regulated in miR472a overexpressing plants. Furthermore, five phased, secondary, small interfering RNAs (phasiRNAs) were confirmed in the miR472a overexpressing and STTM472a lines, triggering phasiRNAs predicted to enhance NBS-LRR silencing. Taken together, our results revealed that ptc-miR472a exerts a key role in plant immunity to C. gloeosporioides and C. chrysosperma by targeting NBS-LRR transcripts. This study provides a new strategy and method in plant breeding to improve plant disease resistance.
Microplastics (MPs) are widely distributed in the global environment, entering and accumulating in organisms in various ways and posing health threats. MPs can damage intestine; however, the ...mechanism by which MPs cause intestinal damage in rats is unclear. Here, rats were exposed to 50 nm PS-NPs or 5 μm PS-MPs for 4 weeks to evaluate the possible effects on intestinal barrier function and exosomal miRNAs expressions. The results showed that PS-NPs or PS-MPs disrupted the gut microbiota and affected gut barrier function at the biological level. In addition, PS-NPs and PS-MPs altered the composition of exosomal miRNAs in the intestinal and serum. Both PS-NPs and PS-MPs decreased the expression of miR-126a-3p in the intestinal and serum exosomes, which is an important signalling molecule involved in MPs induced gut barrier function disorder. More importantly, both in vitro and in vivo experiments indicated that miR-126a-3p was closely related to oxidative damage of intestinal cells through the PI3K-Akt pathway and eventually promote cell apoptosis by regulating the target gene of PIK3R2. Our study suggested that PS-NPs and PS-MPs could affect rat intestinal barrier function through an exosomal miRNA mediated pathway.
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•PS-NPs and PS-MPs altered the exosomal miRNAs in the intestine and serum of rats;•MPs produced oxidative damage by regulating the expression of PIK3R2 in the gut;•MPs affected intestinal barrier function via exosomal miR-126a-3p dependent pathway
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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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