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Acute lymphoblastic leukemia (ALL) is the most common cancer in children worldwide. Although ALL patients' overall survival rates in wealthy countries currently surpass 80%, 15–20% of patients still experience relapse. The underlying mechanisms of relapse are still not fully understood, and little progress has been made in treating refractory or relapsed disease. Disease relapse and treatment failure are common causes of leukemia-related death. In ALL relapse, several gene signatures have been identified, but it is also important to study miRNAs involved in ALL relapse in an effort to avoid relapse and to achieve better survival rates since miRNAs regulate target genes that participate in signaling pathways involved in relapse, such as those related to drug resistance, survival signals, and antiapoptotic mechanisms. Several miRNAs, such as miR-24, miR-27a, miR-99/100, miR-124, miR-1225b, miR-128b, miR-142-3p, miR-155 and miR-335-3p, are valuable biomarkers for prognosis and treatment response in ALL patients. Thus, this review aimed to analyze the primary miRNAs involved in pediatric ALL relapse and explore the underlying molecular mechanisms in an effort to identify miRNAs that may be potential candidates for anti-ALL therapy soon. [ABSTRACT FROM AUTHOR]

The microRNA (miR)-29 family has been deregulated in several types of hematologic malignancies. However, role of this family and their target genes DNMT3A (DNA methyltransferase 3A) and TET2 (Ten-Eleven Translocation 2) remains unclear. Here, we have made an attempt to determine the relative expression levels of three miRNAs and target genes in patients with newly diagnosed Multiple myeloma (MM) using quantitative real-time PCR. Moreover, the expression levels of selected miRNAs and genes and their correlations with clinical parameters were compared and analyzed. The ROC curve was used to analyze their diagnostic efficacy for MM. The expression level of hsa-miR-29b-3p was significantly higher in patients with newly diagnosed MM compared with the control group. ROC analysis showed that hsa-miR-29b-3p demonstrated a moderate diagnostic power in MM. The relative expression level of hsa-miR-29b-3p in patients with high LDH levels was markedly reduced compared to that in patients with normal and low LDH levels. DNMT3A expression level was significantly increased in patients with high LDH levels and patients with lambda light chain. Our results indicate that hsa-miR-29b-3p may be used as a potential biomarker in the diagnosis of MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Dysregulated microRNA (miRNA) expression has been described in the initiation and progression of a wide spectrum of hematologic malignancies. Moreover, aberrant miRNA expression patterns have been shown to be involved in severe post-transplant complications in patients receiving hematopoietic stem cell transplantations (HSCT), suggesting their use as promising diagnostic and prognostic biomarkers for acute graft-versus-host disease (aGvHD). Recently, activation or inhibition of deregulated miRNAs appears to be an attractive therapeutic option for increasing treatment efficacy. Further research concerning the associations between alterations in miRNA levels and malignant hematopoiesis and treatment response might bring new possibilities for specific miRNA-based approaches to improve the outcomes for hematologic cancer patients. Hematologic malignancies are a group of neoplastic conditions that can develop from any stage of the hematopoiesis cascade. Small non-coding microRNAs (miRNAs) play a crucial role in the post-transcriptional regulation of gene expression. Mounting evidence highlights the role of miRNAs in malignant hematopoiesis via the regulation of oncogenes and tumor suppressors involved in proliferation, differentiation, and cell death. In this review, we provide current knowledge about dysregulated miRNA expression in the pathogenesis of hematological malignancies. We summarize data about the clinical utility of aberrant miRNA expression profiles in hematologic cancer patients and their associations with diagnosis, prognosis, and the monitoring of treatment response. Moreover, we will discuss the emerging role of miRNAs in hematopoietic stem cell transplantation (HSCT), and severe post-HSCT complications, such as graft-versus-host disease (GvHD). The therapeutical potential of the miRNA-based approach in hemato-oncology will be outlined, including studies with specific antagomiRs, mimetics, and circular RNAs (circRNAs). Since hematologic malignancies represent a full spectrum of disorders with different treatment paradigms and prognoses, the potential use of miRNAs as novel diagnostic and prognostic biomarkers might lead to improvements, resulting in a more accurate diagnosis and better patient outcomes. [ABSTRACT FROM AUTHOR]

miRNAs are some of the most well-characterized regulators of gene expression. Integral to several physiological processes, their aberrant expression often drives the pathogenesis of both benign and malignant diseases. Similarly, DNA methylation represents an epigenetic modification influencing transcription and playing a critical role in silencing numerous genes. The silencing of tumor suppressor genes through DNA methylation has been reported in many types of cancer and is associated with tumor development and progression. A growing body of literature has described the crosstalk between DNA methylation and miRNAs as an additional layer in the regulation of gene expression. Methylation in miRNA promoter regions inhibits its transcription, while miRNAs can target transcripts and subsequently regulate the proteins responsible for DNA methylation. Such relationships between miRNA and DNA methylation serve an important regulatory role in several tumor types and highlight a novel avenue for potential therapeutic targets. In this review, we discuss the crosstalk between DNA methylation and miRNA expression in the pathogenesis of cancer and describe how miRNAs influence DNA methylation and, conversely, how methylation impacts the expression of miRNAs. Finally, we address how these epigenetic modifications may be leveraged as biomarkers in cancer. [ABSTRACT FROM AUTHOR]

Background: Noncoding RNAs such as microRNAs (miRNAs) have attracted attention as biological pathway regulators, which differ from chromosomal translocations and gene point mutations. Their involvement in the molecular mechanisms underlying light chain (AL) amyloidosis pathogenesis is yet to be elucidated. Aims: To decipher specific miRNA expression profile in AL‐amyloidosis and to examine how miRNAs are involved in AL pathogenesis. Methods: The expression profile of miRNAs and mRNA from bone marrow (BM)‐derived CD138+ cells were determined using the NanoString nCounter assay and RNA‐Seq, respectively. The effect of aberrantly expressed miRNAs on potential molecular targets was analyzed by qRT‐PCR, Western blot, Mito‐potential assay, and Annexin‐PI staining. Results: Genes which were significantly differentially expressed between AL‐amyloidosis and MM, were found to be involved in cell growth and apoptotic mechanisms. Specifically, BCL2L1, MCL1, and BCL2 were upregulated in AL‐amyloidosis compared with MM and controls. The levels of miR‐181a‐5p and miR‐9‐5p, which regulate the above‐mentioned genes, were lower in BM samples from AL‐amyloidosis compared with controls, providing a mechanism for BCL2 family gene upregulation. When miR‐9‐5p and miR‐181a‐5p were overexpressed in ALMC1 cells, BCL2L1, MCL1, and BCL2 were downregulated and induced apoptosis. Treatment of ALMC‐1 cells with venetoclax, (BCL‐2 inhibitor), resulted in the upregulation of those miRNAs, the downregulation of BCL2, MCL1, and BCL2L1 mRNA and protein levels, and subsequent apoptosis. Conclusion: Our findings suggest that miR‐9‐5p and miR‐181a‐5p act as tumor‐suppressors whose downregulation induces anti‐apoptotic mechanisms underlying the pathogenesis of AL‐amyloidosis. The study highlights the post‐transcriptional regulation in AL‐amyloidosis and provides pathogenetic evidence for the potential use of BCL‐2 inhibitors in this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: MicroRNAs (miRNAs) have been under the spotlight for the last three decades. These non-coding RNAs seem to be dynamic regulators of mRNA stability and translation, in addition to interfering with transcription. Circulating miRNAs play a critical role in cell-to-cell interplay; therefore, they can serve as disease biomarkers. Meta-analysis of published data revealed that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against acute lymphoblastic leukemia (ALL) in children. Reanalysis of small RNA-seq data with novel tools identified significantly overexpressed members of the miR-128, miR-181, miR-130 and miR-17 families and significantly lower expression of miR-30, miR-24-2 and miR143~145 clusters, miR-574 and miR-618 in pediatric T-ALL cases compared with controls. Inconsistencies in methodology and study designs in most published material preclude reproducibility, and further cohort studies need to be conducted in order to empower novel tools, such as ALLSorts and RNAseqCNV. MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against ALL occurrence in children; (ii) no significant association between rs2910164 genotypes in miR-146a and childhood ALL; and (iii) SNPs in DROSHA, miR-449b, miR-938, miR-3117 and miR-3689d-2 genes seem to be associated with susceptibility to B-ALL in childhood. A review of published literature on differential expression of miRNAs in children with ALL compared with controls revealed a significant upregulation of the miR-128 family, miR-130b, miR-155, miR-181 family, miR-210, miR-222, miR-363 and miR-708, along with significant downregulation of miR-143 and miR-148a, seem to have a definite role in childhood ALL development. MicroRNA signatures among childhood ALL subtypes, along with differential miRNA expression patterns between B-ALL and T-ALL cases, were scrutinized. With respect to T-ALL pediatric cases, we reanalyzed RNA-seq datasets with a robust and sensitive pipeline and confirmed the significant differential expression of hsa-miR-16-5p, hsa-miR-19b-3p, hsa-miR-92a-2-5p, hsa-miR-128-3p (ranked first), hsa-miR-130b-3p and -5p, hsa-miR-181a-5p, -2-3p and -3p, hsa-miR-181b-5p and -3p, hsa-miR-145-5p and hsa-miR-574-3p, as described in the literature, along with novel identified miRNAs. [ABSTRACT FROM AUTHOR]

Small noncoding RNAs, as post-translational regulators of many target genes, are not only markers of neoplastic disease initiation and progression, but also markers of response to anticancer therapy. Hundreds of miRNAs have been identified as biomarkers of drug resistance, and many have demonstrated the potential to sensitize cancer cells to therapy. Their properties of modulating the response of cells to therapy have made them a promising target for overcoming drug resistance. Several methods have been developed for the delivery of miRNAs to cancer cells, including introducing synthetic miRNA mimics, DNA plasmids containing miRNAs, and small molecules that epigenetically alter endogenous miRNA expression. The results of studies in animal models and preclinical studies for solid cancers and hematological malignancies have confirmed the effectiveness of treatment protocols using microRNA. Nevertheless, the use of miRNAs in anticancer therapy is not without limitations, including the development of a stable nanoconstruct, delivery method choices, and biodistribution. The aim of this review was to summarize the role of miRNAs in cancer treatment and to present new therapeutic concepts for these molecules. Supporting anticancer therapy with microRNA molecules has been verified in numerous clinical trials, which shows great potential in the treatment of cancer. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are the mainstay of treatment of hormone receptor+/human epidermal growth factor receptor 2-patients with advanced breast cancer (ABC). Despite improvements in overall survival, most patients experience disease progression. Biomarkers derived from a liquid biopsy are appealing for their potential to detect resistance to treatment earlier than computed tomography imaging. However, clinical data concerning microRNAs (miRNAs/miRs) in the context of CDK4/6is are lacking. Thus, the present study assessed the use of miRNAs in patients with ABC treated with CDK4/6is. Patients treated for ABC with CDK4/6is between June and August 2022 were eligible. miRNA expression analyses were performed using a TaqMan™ low-density miRNA array. A total of 80 consecutive patients with ABC treated with CDK4/6is at Maria Sklodowska-Curie National Research Institute of Oncology (Gliwice, Poland) were assessed, with 14 patients diagnosed with progressive disease at the time of sampling, 55 patients exhibited clinical benefit from CDK4/6i treatment and 11 patients were at the beginning of CDK4/6i treatment. Patients with disease progression had significantly higher levels of miR-21 (P=0.027), miR-34a (P=0.011), miR-193b (P=0.032), miR-200a (P=0.027) and miR-200b (P=0.003) compared with patients who benefitted from CDK4/6i treatment. Significantly higher levels of miR-34a expression were observed in patients with progressive disease than in patients beginning treatment (P=0.031). The present study demonstrated the potential innovative role of circulating miRNAs during CDK4/6i treatment. Plasma-based expression of miR-21, −34a, −193b, −200a and −200b effectively distinguished patients with ABC who responded to CDK4/6i treatment from patients who were resistant. However, longitudinal studies are required to verify the predictive and prognostic potential of miRNA. [ABSTRACT FROM AUTHOR]

Purpose: T-cell acute lymphoblastic leukemia (T-ALL) affects lymphoid cells. Previous studies have reported that miRNAs play a significant role in T-ALL prognosis and have the potential to function as biomarkers in T-ALL. Therefore, this systematic review and meta-analysis study was designed to evaluate the overall prognostic impact of miRNAs in T-ALL patients. Methods: Eligible studies published between Jan 2010 and April 2018 were retrieved from online bibliographic databases based on multiple keywords to generate search strings. Meta-analysis was performed using the outcome measure, Hazard Ratio (HR). A survival analysis of all studies was conducted and a subsequent forest plot was generated to evaluate the pooled effect size, across all T-ALL patients. Subgroup analysis was conducted based on demographic characteristics and commonly represented miRNAs among the included studies. Results: A total of 17 studies were included for systematic review, among which 16 studies were eligible for meta-analysis, which, in total discussed 32 different miRNAs. The mean effect size of HR value was 0.929 (CI 0.878– 0984), which indicates a decrease in risk of death by 7.1%. The analysis was based on the random effects model with the heterogeneity measure index (I 2) being 84.92%. The pooled effect size (HR) of upregulated and downregulated miRNA expressions on survival outcome in the T-ALL patient was 0.787 (CI 0.732– 0.845) and 1.225 (CI 1.110– 1.344) respectively. The subgroup analysis was performed based on demographic characteristics (age, gender, lactate dehydrogenase, WBC count) and expression of miR221 and miR46a. Conclusion: Our systematic review and meta-analysis findings suggest that the overall miRNA expression is potentially associated with a decreased likelihood of death in T-ALL patients. Although our findings are inconclusive, the results point toward miRNA expression allowing for prognostic evaluation of T-ALL patients. [ABSTRACT FROM AUTHOR]

Radiotherapy is commonly used to treat lung cancer but may not kill all cancer cells, which may be attributed to the radiotherapy resistance that often occurs in non‑small cell lung cancer (NSCLC). At present, the molecular mechanism of radio‑resistance remains unclear. Neuropilin 1 (NRP1), a co‑receptor for vascular endothelial growth factor (VEGF), was demonstrated to be associated with radio‑resistance of NSCLC cells via the VEGF‑phosphoinositide 3‑kinase‑nuclear factor‑κB pathway in our previous study. It was hypothesized that certain microRNAs (miRs) may serve crucial functions in radio‑sensitivity by regulating NRP1. Bioinformatics predicted that NRP1 was a potential target of miR‑9, and this was validated by luciferase reporter assays. Functionally, miR‑9‑transfected A549 cells exhibited a decreased proliferation rate, increased apoptosis rate and attenuated migratory and invasive abilities. Additionally, a high expression of miR‑9 also significantly enhanced the radio‑sensitivity of A549 cells in vitro and in vivo. These data improve understanding of the mechanisms of cell radio‑resistance, and suggest that miR‑9 may be a molecular target for the prediction of radio‑sensitivity in NSCLC. [ABSTRACT FROM AUTHOR]

Innate immune cells form an integrative component of the tumor microenvironment (TME), which can control or prevent tumor initiation and progression, due to the simultaneous processing of both anti- and pro-growth signals. This decision-making process is a consequence of gene expression changes, which are in part dependent on post-transcriptional regulatory mechanisms. In this context, microRNAs have been shown to regulate both recruitment and activation of specific tumor-associated immune cells in the TME. This review aims to describe the most important microRNAs that target cancer-related innate immune pathways. The role of exosomal microRNAs in tumor progression and microRNA-based therapeutic strategies are also discussed. [ABSTRACT FROM AUTHOR]

The ability to reprogram the transcriptional circuitry by remodeling the three-dimensional structure of the genome is exploited by cancer cells to promote tumorigenesis. This reprogramming occurs because of hereditable chromatin chemical modifications and the consequent formation of RNA-protein-DNA complexes that represent the principal actors of the epigenetic phenomena. In this regard, the deregulation of a transcribed non-coding RNA may be both cause and consequence of a cancer-related epigenetic alteration. This review summarizes recent findings that implicate microRNAs in the aberrant epigenetic regulation of cancer cells. [ABSTRACT FROM AUTHOR]

microRNAs (miRNAs) and DNA methylation are the 2 epigenetic modifications that have emerged in recent years as the most critical players in the regulation of gene expression. Compelling evidence has indicated the roles of miRNAs and DNA methylation in modulating cellular transformation and tumorigenesis. miRNAs act as negative regulators of gene expression and are involved in the regulation of both physiologic conditions and during diseases, such as cancer, inflammatory diseases, and psychiatric disorders, among others. Meanwhile, aberrant DNA methylation manifests in both global genome changes and in localized gene promoter changes, which influences the transcription of cancer genes. In this review, we described the mutual regulation of miRNAs and DNA methylation in human cancers. miRNAs regulate DNA methylation by targeting DNA methyltransferases or methylation-related proteins. On the other hand, both hyper- and hypo-methylation of miRNAs occur frequently in human cancers and represent a new level of complexity in gene regulation. Therefore, understanding the mechanisms underlying the mutual regulation of miRNAs and DNA methylation may provide helpful insights in the development of efficient therapeutic approaches. [ABSTRACT FROM PUBLISHER]

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with increasing incidence and high mortality. Surgical resection is the only potentially curative treatment of patients with PDAC. Because of the late presentation of the disease, about 20 percent of patients are candidates for this treatment. The average survival of resected patients is between 12 and 20 months, with a high probability of relapse. Standard chemo and radiation therapies do not offer significant improvement of the survival of these patients. Furthermore, novel treatment options aimed at targeting oncogenes or growth factors in pancreatic cancer have proved unsuccessful. Thereby, identifying new biomarkers that can detect early stages of this disease is of critical importance. Among these biomarkers, microRNAs (miRNAs) have supplied a profitable recourse and become an attractive focus of research in PDAC. MiRNAs regulate many genes involved in the development of PDAC through mRNA degradation or translation inhibition. The possibility of intervention in the molecular mechanisms of miRNAs regulation could begin a new generation of PDAC therapies. This review summarizes the reports describing miRNAs involvement in cellular processes involving pancreatic carcinogenesis and their utility in diagnosis, survival and therapeutic potential in pancreatic cancer. [ABSTRACT FROM AUTHOR]

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MicroRNAs are a family of small noncoding RNAs that regulate the expression of their target proteins at the posttranscriptional level. Their functions cover almost every aspect of cell physiology. However, the roles of microRNAs in fetal lung development are not completely understood. The objective of this study is to investigate the regulation and molecular mechanisms of alveolar epithelial cell maturation during fetal lung development by miR-124. We discovered that miR-124 was downregulated during rat fetal lung development and predominantly expressed in the epithelial cells at late stage of the lung development. Overexpression of miR-124 with an adenovirus vector led to the inhibition of epithelial maturation in rat fetal lung organ cultures and fetal alveolar epithelial type II cells, as demonstrated by a decrease in the type II cell marker expression and an increase in glycogen content. We further demonstrated by luciferase reporter assays that miR-124 inhibited the NF-αB, cAMP/PKA, and MAPK/ERK pathways. In addition, nuclear factor I/B (NFIB), a critical protein in fetal lung maturation, was validated as a direct target of miR-124. Furthermore, miR-124 expression was induced by the Wnt/β-catenin signaling pathway through a direct interaction of LEF1 and the miR-124 promoter region. We concluded that miR-124 downregulation is critical to fetal lung epithelial maturation and miR-124 inhibits this maturation process at least partially through the inhibition of NFIB. [ABSTRACT FROM AUTHOR]

Background MicroRNAs (miRNAs) are endogenous small (19-24 nt long) noncoding RNAs that regulate gene expression in a sequence specific manner. An increasing association between miRNA and cancer has been recently reported. Hepatocellular carcinoma (HCC), as the fifth most common cancer and the most common cause of death in men, has become the third leading cause of cancer-related deaths globally. In this study, we investigated the miR-9 expression in HCC to evaluate their value in prognosis of this tumor. Methods The expression of miR-9 in matched normal and tumor tissues of HCC was evaluated using a quantitative real-time RT-PCR. A Kaplan-Meier survival curve was generated following a log-rank test. Results It was observed that miR-9 expression was upregulated in HCC tissues compared with noncancerous liver tissues (7.26 - 1.30 vs. 3.14 - 1.08, P < 0.001). The up-regulation of miR-9 in HCC cancer tissues was also significantly correlated with aggressive clinicopathological features. We found that the patients with high miR-9 expression have a higher tumor staging (P = 0.0389) and are in higher risk of venous infiltration (P < 0.0001). Moreover, the results of Kaplan-Meier analyses showed that HCC patients with the high miR-9 expression tend to have shorter overall survival (P < 0.0001). The multivariate analysis clearly indicated that the high miR-9 expression in biopsy samples may be considered as an independent prognostic factor in HCC for decreased survival (4.28; 95%CI, 2.77-7.23, P < 0.001). Conclusion Our data indicate the potential of miR-9 as a novel prognostic biomarker for HCC. Large well-designed studies with diverse populations and functional evaluations are warranted to confirm and extend our findings. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that control the expression of many target messenger RNAs (mRNAs) involved in normal cell functions (differentiation, proliferation and apoptosis). Consequently their aberrant expression and/or functions are related to pathogenesis of many human diseases including cancers. Haematopoiesis is a highly regulated process controlled by a complex network of molecular mechanisms that simultaneously regulate commitment, differentiation, proliferation, and apoptosis of hematopoietic stem cells (HSC). Alterations on this network could affect the normal haematopoiesis, leading to the development of haematological malignancies such as lymphomas. The incidence of lymphomas is rising and a significant proportion of patients are refractory to standard therapies. Accurate diagnosis, prognosis and therapy still require additional markers to be used for diagnostic and prognostic purpose and evaluation of clinical outcome. The dysregulated expression or function of miRNAs in various types of lymphomas has been associated with lymphoma pathogenesis. Indeed, many recent findings suggest that almost all lymphomas seem to have a distinct and specific miRNA profile and some miRNAs are related to therapy resistance or have a distinct kinetics during therapy. MiRNAs are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum where they are highly stable and quantifiable within the diagnostic laboratory at each consultation. Accordingly they could be specific biomarkers for lymphoma diagnosis, as well as useful for evaluating prognosis or disease response to the therapy, especially for evaluation of early relapse detection and for greatly assisting clinical decisions making. Here we summarize the current knowledge on the role of miRNAs in normal and aberrant lymphopoiesis in order to highlight their clinical value as specific diagnosis and prognosis markers of lymphoid malignancies or for prediction of therapy response. Finally, we discuss their controversial therapeutic role and future applications in therapy by modulating miRNA. [ABSTRACT FROM AUTHOR]

Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular communication. Like practically all other cellular processes, genes associated in features of ageing are regulated by miRNAs. In this review, I will outline each of the features of ageing, together with examples of specific miRNAs that have been demonstrated to be involved in each one. This will demonstrate the interconnected nature of the regulation of transcripts involved in human ageing, and the role of miRNAs in this process. Definition of the factors involved in degeneration of organismal, tissue and cellular homeostasis may provide biomarkers for healthy ageing and increase understanding of the processes that underpin the ageing process itself. [ABSTRACT FROM AUTHOR]

Background:Nasopharyngeal carcinoma (NPC) has a distinctive geographic distribution and is characterised by its strong tendency of metastasis. We aimed to examine the microRNA (miRNA) expression profiles in plasma samples of NPC patients to explore their clinical significance in disease development and progression.Methods:This study was divided into four steps: (1) confirmation of differentially expressed miRNAs using microarray analysis and quantitative PCR validation; (2) comparison of plasma miR-9 levels during NPC progression; (3) evaluation of the predictive performance of plasma miR-9 as a biomarker for NPC metastasis; and (4) comparison of plasma miR-9 levels between pre- and post-treatment samples.Results:Plasma microarray profiling identified 33 differentially expressed miRNAs between NPC patients and healthy volunteers. The significantly declined level of miR-9 in NPC patients was confirmed through two-stage validation. The low level of plasma miR-9 was significantly correlated with worse lymphatic invasion and advanced TNM stage. The plasma miR-9 could distinguish locoregional from metastatic NPC cases with a high sensitivity and specificity. Furthermore, the plasma miR-9 level was significantly elevated in post-treatment plasma compared with those pre-treatment samples.Conclusion:Our study reports that plasma miR-9 may serve as a useful biomarker to predict NPC metastasis and to monitor tumour dynamics. [ABSTRACT FROM AUTHOR]

Aberrant expression of MIR9 predicts a poor prognosis in acute myelogenous leukemia. To evaluate its clinical significance in acute lymphoblastic leukemia, we analyzed expression levels of MIR9 in bone marrow samples from patients with acute lymphoblastic leukemia and compared them to those in normal bone marrow cells. Approximately 20% of them showed higher expression compared with controls. There was a tendency that patients who showed overexpression of MIR9 underwent worse clinical courses, but without statistical significance. However, when the analyses were restricted to patients who did not receive a stem cell transplant, overexpression of MIR9 was significantly associated with worse overall survival. Interestingly, exaggerated MIR9 expression and higher white blood cell count at presentation were independent unfavorable prognostic factors in all patients for overall survival by multivariate analysis. The presence of higher MIR9 expression could be a useful indicator for treatment stratification. [ABSTRACT FROM AUTHOR]

Background:MicroRNAs alter multiple cell processes and thus influence tumour carcinogenesis and progression. MiR-100 and miR-99a have been reported to be aberrantly expressed in acute leukaemia. In this study, we focused on their functions in acute lymphoblastic leukaemia (ALL) and the molecular networks in which they are involved.Methods:MiR-100 and miR-99a expression levels were measured in acute leukaemia patients by qRT-PCR. Kaplan−Meier analysis and log-rank tests were used to calculate the survival rate. Three human ALL cell lines were studied. Apoptosis and proliferation were analysed using siRNA transfection, western blot and flow cytometry.Results:In vivo, miR-100 and miR-99a were down-regulated in 111 ALL patients, especially in high-risk groups; their expression levels were correlated with the patient's 5-year survival. In vitro, the restoration of miR-100 and miR-99a in ALL cells suppressed cell proliferation and increased dexamethasone-induced cell apoptosis. Ectopic expression of miR-100 and miR-99a targeted FK506-binding protein 51 (FKBP51) and, in turn, influenced glucocorticoid receptor (GR) activity. Meanwhile, miR-100 and miR-99a overexpression inhibited the expression of IGF1R and mTOR and their downstream oncogene MCL1.Conclusion:MiR-100 and miR-99a have critical roles in altering cellular processes by targeting both the FKBP51 and IGF1R/mTOR signalling pathways in vitro and might represent a potential novel strategy for ALL treatment. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukaemia ( ALL) is the most common paediatric malignancy. Although 90% of patients are now long-term survivors, the remaining 10% have poor outcome predominantly due to drug resistance. In this study, we carried out genome-wide micro RNA (mi RNA) microarray analysis on diagnostic bone marrow samples to determine mi RNA expression profiles associated with poor outcome in ALL. A reduced expression of MIR335 was identified as the most significant mi RNA abnormality associated with poor outcome. It is well known that glucocorticoid ( GC) resistance is one of the major reasons contributing to poor outcome. We show that exogenous expression of MIR335 in ALL cells increases sensitization to prednisolone-mediated apoptosis. Moreover, we demonstrate that MAPK1 is a novel target of MIR335, and that MEK/ ERK inhibitor treatment enhanced prednisolone-induced cell death through the activation of BIM ( BCL2L11). These results provide a possible underlying molecular mechanism to explain the association between reduced MIR335 with poor clinical outcome, and suggest that approaches to re-introduce MIR335 expression or override MAPK1 activity may offer promising therapeutic strategies in the treatment of ALL. [ABSTRACT FROM AUTHOR]

Heart failure is a syndrome resulting from a complex genetic predisposition and multiple environmental factors, and is a leading cause of morbidity and mortality. It is frequently accompanied by changes in heart mass, size, and shape, a process known as pathological cardiac remodeling. At the molecular level, these changes are preceded and accompanied by a specific gene expression program characterized by expression of certain 'fetal' genes. This re-expression of fetal genes in the adult heart contributes to the development of the syndrome. Therefore, counteracting the gene expression changes occurring in heart failure could be a therapeutic approach for this pathology. One mechanism of gene expression regulation that has gained importance is epigenetics. This review gives an overview of the roles of some epigenetic mechanisms, such as DNA methylation, histone modifications, ATP-dependent chromatin remodeling, and microRNA-dependent mechanisms, in heart failure. [ABSTRACT FROM AUTHOR]

MicroRNA-9 (miR-9) is emerging as a critical regulator of organ development and neurogenesis. It is also deregulated in several types of solid tumors; however, its role in hematopoiesis and leukemogenesis is not yet known. Here we show that miR-9 is detected in hematopoletic stem cells and hematopoietic progenitor cells, and that its expression increases during hematopoletic differentiation. Ectopic expression of miR-9 strongly accelerates terminal myelpoiesis and promotes apoptosis in vitro and in vivo. Conversely, in hematopoietic progenitor cells, the inhibition of miR-9 with a miRNA sponge blocks myelopoiesis. Ecotropic viral integration site 1 (EVI1), required for normal embryogenesis, is considered an oncogene because its inappropriate up-regulation induces malignant transformation in solid and hematopoietic cancers. Here we show that EVI1 binds to the promoter of miR-9-3, leading to DNA hypermethylation of the promoter and repression of miR-9. Moreover, miR-9 expression reverses a myeloid differentiation block that is induced by EVI1. Our findings indicate that EVI1, when inappropriately expressed, delays or blocks myeloid differentiation at least in part by DNA hypermethylation and down-regulation of miR-9. It was reported that Forkhead box class O genes (FoxOs) inhibit myeloid differentiation and prevent differentiation of leukemia-initiating cells. Here we identify both FoxO1and FoxO3 as direct targets of miR-9 in hematopoietic cells and find that up-regulation of FoxO3 inhibits miR-9-induced myelopoiesis. These results reveal a unique role of miR-9 in myeIopoiesis and in the pathogenesis of EVI1-induced myeloid neoplasms and provide insights into the epigenetic regulation of miR9 in tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: MIR129-2 has been shown to be a tumor suppressor microRNA hypermethylated in epithelial cancers. Patients and methods: Epigenetic inactivation of MIR129-2 was studied by methylation-specific PCR (MSP) in 13 cell lines (eight myeloma and five lymphoma), 15 normal controls and 344 primary samples including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) at diagnosis, MM at relapse/progression, and monoclonal gammopathy of undetermined significance (MGUS). Expression of MIR129 and its target, SOX4, in cell lines was measured before and after hypomethylating treatment and MIR129 overexpression. MIR129 expression was correlated with MIR129-2 methylation status in primary lymphoma samples. Tumor suppressor function of MIR129 was demonstrated by MTT and trypan blue exclusion assay after MIR129 overexpression. Results: The sensitivity of the methylated-MSP was one in 103. Different MSP statuses, including complete methylation, partial methylation, and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. All five lymphoma and seven of eight myeloma cell lines showed complete and partial MIR129-2 methylation. In primary samples, MIR129-2 methylation was absent in AML and CML, but detected in 5% ALL, 45.9% CLL, 49.5% MM at diagnosis, and 59.1% NHL. In CLL, MIR129-2 methylation adversely impacted on survival (p=0.004). In MM, MIR129-2 methylation increased from 27.5% MGUS to 49.5% MM at diagnosis and 41.5% at relapse/ progression (p=0.023). In NHL, MIR129-2 methylation was associated with MIR124-1 and MIR203 methylation (p<0.001), and lower MIR129 expression (p=0.009). Hypomethylation treatment of JEKO-1, homozygously methylated for MIR129-2, led to MIR129-2 demethylation and MIR129 re-expression, with downregulation of SOX4 mRNA. Moreover, MIR129 overexpression in both mantle cell lines, JEKO-1 and GRANTA-519, inhibited cellular proliferation and enhanced cell death, with concomitant SOX4 mRNA downregulation. Conclusions: MIR129-2 is a tumor suppressive microRNA frequently methylated in lymphoid but not myeloid malignancies, leading to reversible MIR129-2 silencing. In CLL, MIR129-2 methylation was associated with an inferior survival. In MM, MIR129-2 methylation might be acquired during progression from MGUS to symptomatic MM. In NHL, MIR129-2 methylation might collaborate with MIR124-1 and MIR203 methylation in lymphomagenesis. [ABSTRACT FROM AUTHOR]

The relatively recent discovery of micro RNAs (mi RNAs) has exposed an extra layer of gene expression regulation that affects many physiological and pathological processes of biology. Dysregulation of mi RNAs is a ubiquitous feature of cancer in general, including lymphomas. The identity of these aberrantly-expressed mi RNAs has been thoroughly investigated in all but a few types of lymphomas, however their functional role in lymphomagenesis much less so. This review focuses on those mi RNAs that have an experimentally confirmed functional role in the pathogenesis of the most frequent forms of lymphoma. In particular, the MIR15A/16-1 cluster, MIR21, MIR155, MIR17 HG ( MIR17-92 cluster) , MIR34A and MIR125B, which have in vivo animal model evidence for their involvement in lymphomagenesis, are highlighted. [ABSTRACT FROM AUTHOR]

Background:Whether methylation of the microRNA (mir)-124-3 CpG island is of relevance for the clinical course of a solid cancer and whether it shows association with clinicopathology or survival of patients with renal cell cancer (RCC) is not known as yet.Methods:In a cross-sectional study, relative methylation of mir-124-3 was measured in 111 RCC samples and 77 paired normal appearing tissues using quantitative methyl-specific PCR. Results were statistically compared with tumour histology, clinicopathological parameters and disease recurrence.Results:We found tumour-specific hypermethylation of mir-124-3 in samples of RCCs with clear cell histology (ccRCC) compared with paired normal appearing tissues (P<0.0001). Methylation was significantly increased in tumours with state of advanced disease (P<0.0001). Higher relative methylation was associated with worse recurrence-free survival in both univariate (hazard ratio=9.37; P=0.0005) as well as bivariate Cox regression analyses considering age, sex, diameter of tumours and state of advanced disease, metastasis and lymph node metastases as covariates (hazard ratios=5.9-18.2; P-values of 0.0003-0.008).Conclusion:We identified mir-124-3 CpG islands (CGI) methylation as a relevant epigenetic mark for ccRCC thus underlining the need for functional studies of potentially affected signalling pathways in kidney tumour models. Methylation of mir-124-3 is suggested as an independent prognosticator for ccRCC. [ABSTRACT FROM AUTHOR]

Abstract: DNA methylation plays a key role in the silencing of numerous cancer-related genes, thereby affecting a number of vital cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion and angiogenesis. Also widely altered in human malignancies is the expression of microRNAs (miRNAs), a class of small noncoding RNAs that act as posttranscriptional regulators of gene expression. Furthermore, emerging evidence now supports the idea that DNA methylation is crucially involved in the dysregulation of miRNAs in cancer. This is in part the result of technological advances that enable more comprehensive analysis of miRNA expression profiles and the epigenome in cancer cells, which has led to the identification of a number of epigenetically regulated miRNAs. As with protein-coding genes, it appears that miRNA genes involved in regulating cancer-related pathways are silenced in association with CpG island hypermethylation. In addition, methylation in CpG island shore regions and DNA hypomethylation also appear to contribute to miRNA dysregulation in cancer. Aberrant DNA methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Moreover, re-expression of miRNAs and the replacement of tumor suppressive miRNAs using miRNA mimics or expression vectors could be effective approaches to cancer therapy. [Copyright &y& Elsevier]

Epigenetic changes, including DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, numerous studies have shown that noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs exert tumor-suppressive or oncogenic effects. In addition, it now appears that long ncRNAs may be causally related to epigenetic dysregulation of critical genes in cancer. Dissection of the relationships between ncRNAs and epigenetic alterations may lead to the development of novel approaches to the diagnosis and treatment of cancer. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are recognized as being central players in many biological processes and cellular pathways. Their roles in disease have been highlighted first by observation of their aberrant expression profiles in human tumors, and then by in vitro and in vivo functional studies in transformed cells and model organisms. One of the most commonly observed features of miRNAs in malignancies is a defect in their production. Although several causes may be associated with this phenomenon, such as upstream oncogenic/tumor-suppressor defects and alterations in the miRNA-processing machinery, epigenetic inactivation is the prime suspect. The number of miRNAs with putative growth-inhibitory functions undergoing promoter CpG island hypermethylation in human cancer is growing fast and more detailed biological studies are necessary. The recognition of miR-124a and miR-34b/c as bona fide tumor-suppressor miRNAs undergoing DNA methylation-associated silencing in a wide spectrum of human neoplasms is a good starting point to be followed by other candidate miRNAs. Most importantly, even at this early stage, the transcriptional repression of miRNAs by hypermethylation of their corresponding promoter loci seems to be a common feature of all human tumors. This will have translational consequences for the management of the disease. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia. [ABSTRACT FROM AUTHOR]

The EGFR-driven cell-cycle pathway has been extensively studied due to its pivotal role in breast cancer proliferation and pathogenesis. Although several studies reported regulation of individual pathway components by microRNAs (miRNAs), little is known about how miRNAs coordinate the EGFR protein network on a global miRNA (miRNome) level. Here,we combined a large-scale miRNA screening approach with a high-throughput proteomic readout and network-based data analysis to identify which miRNAs are involved, and to uncover potential regulatory patterns. Our results indicated that the regulation of proteins by miRNAs is dominated by the nucleotide matching mechanism between seed sequences of the miRNAs and 3'-UTR of target genes. Furthermore, the novel network-analysis methodology we developed implied the existence of consistent intrinsic regulatory patterns where miRNAs simultaneously co-regulate several proteins acting in the same functional module. Finally, our approach led us to identify and validate three miRNAs (miR-124, miR-147 and miR-193a-3p) as novel tumor suppressors that co-target EGFR-driven cell-cycle network proteins and inhibit cell-cycle progression and proliferation in breast cancer. [ABSTRACT FROM AUTHOR]

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models. [ABSTRACT FROM AUTHOR]

Cancer is a complex disease involving alterations of multiple processes, with both genetic and epigenetic features contributing as core factors to the disease. In recent years, it has become evident that non-coding RNAs (ncRNAs), an epigenetic factor, play a key role in the initiation and progression of cancer. MicroRNAs, the most studied non-coding RNAs subtype, are key controllers in a myriad of cellular processes, including proliferation, differentiation, and apoptosis. Furthermore, the expression of miRNAs is controlled, concomitantly, by other epigenetic factors, such as DNA methylation and histone modifications, resulting in aberrant patterns of expression upon the occurrence of cancer. In this sense, aberrant miRNA landscape evaluation has emerged as a promising strategy for cancer management. In this review, we have focused on the regulation (biogenesis, processing, and dysregulation) of miRNAs and their role as modulators of the epigenetic machinery. We have also highlighted their potential clinical value, such as validated diagnostic and prognostic biomarkers, and their relevant role as chromatin modifiers in cancer therapy. [ABSTRACT FROM AUTHOR]

Despite the success of imatinib in advanced gastrointestinal stromal tumor (GIST) patients, 50% of the patients experience resistance within two years of treatment underscoring the need to get better insight into the mechanisms conferring imatinib resistance. Here the microRNA and mRNA expression profiles in primary (imatinib-naïve) and imatinib-resistant GIST were examined. Fifty-three GIST samples harboring primary KIT mutations (exon 9; n = 11/exon 11; n = 41/exon 17; n = 1) and comprising imatinib-naïve (IM-n) (n = 33) and imatinib-resistant (IM-r) (n = 20) tumors, were analyzed. The microRNA expression profiles were determined and from a subset (IM-n, n = 14; IM-r, n = 15) the mRNA expression profile was established. Ingenuity pathway analyses were used to unravel biochemical pathways and gene networks in IM-r GIST. Thirty-five differentially expressed miRNAs between IM-n and IM-r GIST samples were identified. Additionally, miRNAs distinguished IM-r samples with and without secondary KIT mutations. Furthermore 352 aberrantly expressed genes were found in IM-r samples. Pathway and network analyses revealed an association of differentially expressed genes with cell cycle progression and cellular proliferation, thereby implicating genes and pathways involved in imatinib resistance in GIST. Differentially expressed miRNAs and mRNAs between IM-n and IM-r GIST were identified. Bioinformatic analyses provided insight into the genes and biochemical pathways involved in imatinib-resistance and highlighted key genes that may be putative treatment targets. [ABSTRACT FROM AUTHOR]

For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors. [ABSTRACT FROM AUTHOR]