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Immune cells of myeloid origin, including microglia, macrophages, and myeloid-derived suppressor cells adopt immunosuppressive phenotypes that support gliomagenesis. Here, we tested an a priori hypothesis that single nucleotide polymorphisms (SNPs) in genes related to glioma-associated myeloid cell regulation and function are also associated with patient survival after glioma diagnosis. Subjects for this study were 992 glioma patients treated at The University of Texas MD Anderson Cancer Center in Houston, Texas between 1992 and 2008. Haplotype-tagging SNPs in 91 myeloid-associated genes were analyzed for association with survival by Cox regression. Individual SNP- and gene-based tests were performed separately in glioblastoma (WHO grade IV, n = 511) and lower-grade glioma (WHO grade II-III, n = 481) groups. After adjustment for multiple testing, no myeloid-associated gene variants were significantly associated with survival in glioblastoma. Two SNPs, rs147960238 in CD163 (p = 2.2 × 10-5) and rs17138945 in MET (p = 5.6 × 10-5) were significantly associated with survival of patients with lower-grade glioma. However, these associations were not confirmed in an independent analysis of 563 lower-grade glioma cases from the University of California at San Francisco Adult Glioma Study (p = 0.65 and p = 0.41, respectively). The results of this study do not support a role for inherited polymorphisms in myeloid-associated genes in affecting survival of patients diagnosed with glioblastoma or lower-grade glioma.

In the originally published version of this Article, the positions of the final two authors in the author list were inadvertently inverted during the production process. This error has now been corrected in both the PDF and HTML versions of the Article.

The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis. Their mechanisms of action and the factors regulating their expression in cancers are poorly understood. Here we show that high expression of uc.339 correlates with lower survival in 210 non-small cell lung cancer (NSCLC) patients. We provide evidence from cell lines and primary samples that TP53 directly regulates uc.339. We find that transcribed uc.339 is upregulated in archival NSCLC samples, functioning as a decoy RNA for miR-339-3p, -663b-3p, and -95-5p. As a result, Cyclin E2, a direct target of all these microRNAs is upregulated, promoting cancer growth and migration. Finally, we find that modulation of uc.339 affects microRNA expression. However, overexpression or downregulation of these microRNAs causes no significant variations in uc.339 levels, suggesting a type of interaction for uc.339 that we call "entrapping". Our results support a key role for uc.339 in lung cancer.

PurposeWe evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment.Experimental designThirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3-6, and once every other course during courses 7-24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed.ResultsThe overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders.ConclusionsThe combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359-67. ©2016 AACR.

Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.

PurposeThe IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.Experimental design and resultsFirst, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.ConclusionsThese results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.

Although numerous studies highlighted the role of Epstein-Barr Virus (EBV) in B-cell transformation, the involvement of EBV proteins or genome in the development of the most frequent adult leukemia, chronic lymphocytic leukemia (CLL), has not yet been defined. We hypothesized that EBV microRNAs contribute to progression of CLL and demonstrated the presence of EBV miRNAs in B-cells, in paraffin-embedded bone marrow biopsies and in the plasma of patients with CLL by using three different methods (small RNA-sequencing, quantitative reverse transcription PCR [q-RT-PCR] and miRNAs in situ hybridization [miRNA-ISH]). We found that EBV miRNA BHRF1-1 expression levels were significantly higher in the plasma of patients with CLL compared with healthy individuals (p

MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive exploration of the genetic and molecular landscape of the miR-142 genomic locus, highlighting its mutations and dysregulation within hematological malignancies. Finally, we discuss potential avenues for harnessing the therapeutic potential of miR-142 in the context of hematological malignancies. [ABSTRACT FROM AUTHOR]

The view of long noncoding RNAs as nonfunctional "garbage" has been definitely outdated by the large body of evidence indicating this class of ncRNAs as "golden junk", especially in precision oncology. Indeed, in light of their oncogenic role and the higher expression in multiple cancer types compared with paired adjacent tissues, the clinical interest for lncRNAs as diagnostic and/or prognostic biomarkers has been rapidly increasing. The emergence of large‐scale sequencing technologies, their subsequent diffusion even in small research and clinical centers, the technological advances for the detection of low‐copy lncRNAs in body fluids, coupled to the huge reduction of operating costs, have nowadays made possible to rapidly and comprehensively profile them in multiple tumors and large cohorts. In this review, we first summarize some relevant data about the oncogenic role of well‐studied lncRNAs having a clinical relevance. Then, we focus on the description of their potential use as diagnostic/prognostic biomarkers, including an updated overview about licensed patents or clinical trials on lncRNAs in oncology. [ABSTRACT FROM AUTHOR]

Simple Summary: The discovery of microRNAs has revolutionized the world of science and opened up new opportunities in cancer treatment. miRNA dysregulation plays a crucial role in carcinogenesis processes, such as invasion, metastasis, and angiogenesis, in a broad range of cancers. Although the use of miRNA therapy in cancer treatment is promising, its effective and safe application remains one of the most important challenges hindering its clinical use. Novel nanoparticles continue to be developed and used to enable tumor-targeted miRNA delivery. The aim of the present review is to provide insights into the strategies for miRNA-based therapeutics in cancer, focusing on recent in vivo and clinical studies that have used nanoparticles for miRNA delivery. MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20–25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics have entered human clinical trials with promising results, and they are expected to accelerate the transition of miRNAs from the bench to the bedside in the next decade. Here, we present recent perspectives and the newest developments, describing several engineered natural and synthetic novel miRNA nanocarrier formulations and their key in vivo applications and clinical trials. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPIs) have been shown to regulate the gut microbiome and affect the response to immune checkpoint inhibitors (ICIs). Contradictory results on survival have been observed in patients concomitantly treated with ICIs and PPIs. We performed a systematic review and meta-analysis to determine the association between PPI use and survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases, and major oncology conference proceedings were searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI-treated and PPI-free groups of ICI-treated cancer patients were included. Data regarding study and patient characteristics, ICI and PPI treatments, and survival outcomes were extracted. Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using random effects models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among the studies. Results: A total of 33 studies were included, comprising 7383 ICI- and PPI-treated patients and 8574 ICI-treated and PPI-free patients. The pooled HR was 1.31 (95% CI, 1.19–1.44; p < 0.001) for OS and 1.30 (95% CI, 1.17–1.46; p < 0.001) for PFS, indicating a significant negative association between PPI use and survival in ICI-treated patients. Subgroup meta-analyses by factors including cancer type, ICI type, and time window of PPI use revealed that ICI and PPI use impacted survival in patients with non-small cell lung or urothelial cancer, patients treated with anti-PD-1/PD-L1 antibodies, and patients receiving PPI as baseline treatment or 60 days before ICI treatment initiation. Conclusions: PPI use in patients treated with ICIs was associated with shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled and appear to not impact survival if given temporarily after ICI initiation. These observations could provide the basis for clinical guidelines for concomitant PPI and ICI use. [ABSTRACT FROM AUTHOR]

Simple Summary: The genome-wide association study (GWAS) approach to common human disease relies on single nucleotide polymorphisms (SNPs), the most common type of genetic variation in the human genome, and distinguishes "risk" and "healthy" SNP alleles. In parallel with increasing insights into the non-coding genome, emerging studies reveal that most disease-associated SNPs reside within a non-coding sequence, including lncRNA genes. These developments lay the foundation for deciphering the aetiology of complex diseases, including type 2 diabetes (T2D), and its association with an increased risk of certain cancers. Here, deploying a customized annotation pipeline on GWAS datasets, we successfully identified, and characterized, six genetic variants significantly associated with both T2D and cancer in lncRNA or genes and other non-coding regions. These variants suggest evidential proof of a shared genetic architecture between the two diseases, help to functionally explain the casual association of diabetes with cancer, and comprise a potential shortlist of candidate drug targets. Numerous epidemiological studies place patients with T2D at a higher risk for cancer. Many risk factors, such as obesity, ageing, poor diet and low physical activity, are shared between T2D and cancer; however, the biological mechanisms linking the two diseases remain largely unknown. The advent of genome wide association studies (GWAS) revealed large numbers of genetic variants associated with both T2D and cancer. Most significant disease-associated variants reside in non-coding regions of the genome. Several studies show that single nucleotide polymorphisms (SNPs) at or near long non-coding RNA (lncRNA) genes may impact the susceptibility to T2D and cancer. Therefore, the identification of genetic variants predisposing individuals to both T2D and cancer may help explain the increased risk of cancer in T2D patients. We aim to investigate whether lncRNA genetic variants with significant diabetes and cancer associations overlap in the UAE population. We first performed an annotation-based analysis of UAE T2D GWAS, confirming the high prevalence of variants at or near non-coding RNA genes. We then explored whether these T2D SNPs in lncRNAs were relevant to cancer. We highlighted six non-coding genetic variants, jointly reaching statistical significance in T2D and cancer, implicating a shared genetic architecture between the two diseases in the UAE population. [ABSTRACT FROM AUTHOR]

On March 11, 2020, the WHO has declared the coronavirus disease 2019 (COVID-19) a global pandemic. As the last few months have profoundly changed the delivery of health care in the world, we should recognize the effort of numerous comprehensive cancer centers to share experiences and knowledge to develop best practices to care for oncological patients during the COVID-19 pandemic. Patients as well as physicians must be aware of all these constraints and profound social, personal, and medical challenges posed by the tackling of this deadly disease in everyday life in order to adjust to such a completely novel scenario. This review will discuss facing the challenges and the current approaches that cancer centers in Italy and United States are adopting in order to cope with clinical and research activities. [ABSTRACT FROM AUTHOR]

The generation and organization of the invasion front shape of neoplasms is an intriguing problem. The intimate mechanism is not yet understood, but the prevailing theory is that it represents an example of morphogenesis. Morphogenesis requires the presence of specific molecules, known as morphogens (activators and inhibitors), which can diffuse and elicit dose-dependent responses in their target cells. Due to their ability to modulate most of the coding transcriptome, their well-established role in embryogenesis, and their capacity to rapidly move between neighboring and distant cells, we propose microRNAs as inhibitors that could shape the cancer invasion front. In order to explain the genesis of the tumor border, we use Alan Turing's reaction diffusion model, refined by Meinhardt and Gierer. This assumes the existence of an activator called a, and an inhibitor called h, which we hypothesize could be a freely moving microRNA. We used the fractal dimension as a measure of tumor border irregularity. We observed that the change in fractal dimension associates with variations in the diffusion coefficient of the activator (Da) or the inhibitor (Dh). We determined that the fractal dimension remains constant (i.e., the irregularity of the tumor border does not change) across a Dh interval, which becomes narrower as Da rises. We therefore conclude that a change in fractal dimension occurs when the balance between Da and Dh is disrupted. Biologically, this could be explained by a faulty distribution of the inhibitor caused by an abnormal density of the intercellular connection network. From a translational perspective, if experimentally confirmed, our observations can be used for a better diagnosis of cancer aggressiveness. [ABSTRACT FROM AUTHOR]

Background: Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor-targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified.Methods: We quantified miR-27a* in 47 oral cavity squamous cell carcinoma patient samples along with analysis of miR-27a* in 73 oropharyngeal and 66 human papillomavirus-positive (HPV+) samples from The Cancer Genome Atlas. In vivo and in vitro TP53 models engineered to express mutant TP53, along with promoter analysis using chromatin immunoprecipitation and luciferase assays, were used to identify the role of TP53 and TP63 in miR-27a* transcription. An HNSCC cell line engineered to conditionally express miR-27a* was used in vitro to determine effects of miR-27a* on target genes and tumor cells.Results: miR-27a* expression was repressed in 47 oral cavity tumor samples vs matched normal tissue (mean log2 difference = -0.023, 95% confidence interval = -0.044 to -0.002; two-sided paired t test, P = .03), and low miR-27a* levels were associated with poor survival in HPV+ and oropharyngeal HNSCC samples. Binding of ΔNp63α to the promoter led to an upregulation of miR-27a*. In vitro and in vivo findings showed that mutant TP53 represses the miR-27a* promoter, downregulating miR-27a* levels. ΔNp63α and nucleoporin 62, a protein involved in ΔNP63α transport, were validated as novel targets of miR-27a*.Conclusion: Our results characterize a negative feedback loop between TP63 and miR-27a*. Genetic alterations in TP53, a frequent event in HNSCC, disrupt this regulatory loop by repressing miR-27a* expression, promoting tumor survival. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNA) are RNA molecules built from fragments of linear pre-messenger RNAs and other linear RNA species through a process termed "back-splicing" in which the 3' and 5' ends are joined together giving rise to a covalently uninterrupted loop. circRNAs are not new members of the RNA world; they were first discovered in the early 1990s. The novelty is their abundance in the mammalian cells, as recently thousands of circRNAs were discovered and annotated. The biogenesis of circRNAs is a partially characterized process, regulated by three different mechanisms: exon skipping, intron pairing, and RNA-binding proteins. On the other hand, the function of circRNAs remains largely unknown and only a handful of singular reports describe in detail the biological roles of some circular transcripts. In a very short period of time, numerous circRNAs were associated with various cancer types and were also identified in bodily fluids with the potential of being disease-specific biomarkers. In this review, we briefly describe the biogenesis and function of circRNAs and present the circular transcripts that were more than once reported in literature to be associated with cancer. Finally, we point out some of the difficulties encountered in the study of circRNAs in cancer, as we consider that taking these into account could accelerate and improve our understanding of the biologic and translational use of circRNAs in human diseases. [ABSTRACT FROM AUTHOR]

A major mechanism of tumor development and progression is silencing of the patient's immune response to cancer-specific antigens. Defects in the so-called cancer immunity cycle may occur at any stage of tumor development. Within the tumor microenvironment, aberrant expression of immune checkpoint molecules with activating or inhibitory effects on T lymphocytes induces immune tolerance and cellular immune escape. Targeting immune checkpoint molecules such as programmed cell death protein 1 ( PD-1) and its ligand PD-L1 with specific antibodies has proven to be a major advance in the treatment of several types of cancer. Another way to therapeutically influence the tumor microenvironment is by modulating the levels of micro RNAs (mi RNAs), small noncoding RNAs that shuttle bidirectionally between malignant and tumor microenvironmental cells. These small RNA transcripts have two features: (a) their expression is quite specific to distinct tumors, and (b) they are involved in early regulation of immune responses. Consequently, mi RNAs may be ideal molecules for use in cancer therapy. Many mi RNAs are aberrantly expressed in human cancer cells, opening new opportunities for cancer therapy, but the exact functions of these mi RNAs and their interactions with immune checkpoint molecules have yet to be investigated. This review summarizes recently reported findings about mi RNAs as modulators of immune checkpoint molecules and their potential application as cancer therapeutics in clinical practice. [ABSTRACT FROM AUTHOR]

The role of immune response is emerging as a key factor in the complex multistep process of cancer. Tumor microenvironment contains different types of immune cells, which contribute to regulate the fine balance between anti and protumor signals. In this context, mechanisms of crosstalk between cancer and immune cells remain to be extensively elucidated. Interestingly, microRNAs (miRNAs) have been demonstrated to function as crucial regulators of immune response in both physiological and pathological conditions. Specifically, different miRNAs have been reported to have a role in controlling the development and the functions of tumor-associated immune cells. This review aims to describe the most important miRNAs acting as critical modulators of immune response in the context of different solid tumors. In particular, we discuss recent studies that have demonstrated the existence of miRNA-mediated mechanisms regulating the recruitment and the activation status of specific tumor-associated immune cells in the tumor microenvironment. Moreover, various miRNAs have been found to target key cancer-related immune pathways, which concur to mediate the secretion of immunosuppressive or immunostimulating factors by cancer or immune cells. Modalities of miRNA exchange and miRNA-based delivery strategies are also discussed. Based on these findings, the modulation of individual or multiple miRNAs has the potential to enhance or inhibit specific immune subpopulations supporting antitumor immune responses, thus contributing to negatively affect tumorigenesis. New miRNA-based strategies can be developed for more effective immunotherapeutic interventions in cancer. [ABSTRACT FROM AUTHOR]

The role of circulating free microRNAs (cfmiRNAs) as promising tools for cancer screening, prognosis and monitoring of anticancer therapies has been widely studied in the past decades. cfmiRNAs have all the characteristics of the perfect biomarkers owing high stability under storage and handling conditions and being detectable not only in plasma, but in almost all body fluids. Moreover, their levels in plasma are likely to resemble ones in the primary tumor. Recently, viral and plant miRNAs have been found in plasma of healthy individuals through deep sequencing technique, and subsequently the same ones were deregulated in patients. Growing body of literature is recently focusing on understanding the potential cross-kingdom regulation of human mRNAs by miRNAs most likely absorbed with food ingestion. In this article we will review the literature concerning the xenomiRs detected in plasma and their role in influencing cancer onset and progression. XenomiRs could potentially be used not only as early screening tool, but also for patients' prognosis. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are transcripts without protein-coding capacity; initially regarded as 'transcriptional noise', lately they have emerged as essential factors in both cell biology and mechanisms of disease. In this article, we present basic knowledge of lncRNA molecular mechanisms, associated physiological processes and cancer association, as well as their diagnostic and therapeutic value in the form of a decalog: (1) Non-coding RNAs (ncRNAs) are transcripts without protein-coding capacity divided by size (short and long ncRNAs), function (housekeeping RNA and regulatory RNA) and direction of transcription (sense/antisense, bidirectional, intronic and intergenic), containing a broad range of molecules with diverse properties and functions, such as messenger RNA, transfer RNA, microRNA and long non-coding RNAs. (2) Long non-coding RNAs are implicated in many molecular mechanisms, such as transcriptional regulation, post-transcriptional regulation and processing of other short ncRNAs. (3) Long non-coding RNAs play an important role in many physiological processes such as X-chromosome inactivation, cell differentiation, immune response and apoptosis. (4) Long non-coding RNAs have been linked to hallmarks of cancer: (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) enabling replicative immortality; (d) activating invasion and metastasis; (e) inducing angiogenesis; (f) resisting cell death; and (g) reprogramming energy metabolism. (5) Regarding their impact on cancer cells, lncRNAs are divided into two groups: oncogenic and tumor-suppressor lncRNAs. (6) Studies of lncRNA involvement in cancer usually analyze deregulated expression patterns at the RNA level as well as the effects of single nucleotide polymorphisms and copy number variations at the DNA level. (7) Long non-coding RNAs have potential as novel biomarkers due to tissue-specific expression patterns, efficient detection in body fluids and high stability. (8) LncRNAs serve as novel biomarkers for diagnostic, prognostic and monitoring purposes. (9) Tissue specificity of lncRNAs enables the development of selective therapeutic options. (10) Long non-coding RNAs are emerging as commercial biomarkers and therapeutic agents. [ABSTRACT FROM AUTHOR]

Epigenetic alterations have been reported to deregulate the expression of many transcripts, including noncoding RNAs that have no apparent protein-coding capacity. Recently, as the result of numerous studies focused on miRNAs, novel sequencing technologies have made available the transcription profile of the entire human genome. miRNAs as drivers of tumor-suppressive and oncogenic functions have been found to be dysregulated in numerous cancer types. However, the functions of epigenetically regulated genetic elements other than protein-coding genes are still a matter of debate. In this review, the authors focus mainly on describing the epigenetic regulation of miRNAs in cancer. They also discuss the role of miRNAs as potential diagnostic and/or prognostic biomarkers. [ABSTRACT FROM AUTHOR]

The recent discovery of functional cell-free circulating microRNAs (miRNAs) in human body fluids has opened new avenues for the application of non-coding RNAs (ncRNAs) as noninvasive, specific and sensitive biomarkers for cancers and other human diseases. In this review, we explore the concept of circulating miRNAs as hormones, and discuss their potential functions in cellular communication and transferring of signals. We also provide a brief overview of their identification, processing, and potential functions and applications in human diseases. [ABSTRACT FROM AUTHOR]

Non-coding RNAs were previously thought to have little importance because they are not directly translated into a protein like their coding counterparts. However, it was recently found that non-coding RNAs do in fact have a much bigger role than previously thought. They are involved in cancer predisposition, development and progression. MicroRNAs, very short non-coding RNAs, are abnormally expressed in cancer and some harbor mutations that affect expression levels. MicroRNA alterations have been observed in all forms of cancer that have been researched to the current date. MicroRNAs are also located in cancer- associated genomic regions, which have been previously shown to affect gene expression leading to the activation or inhibition of cancer growth. Single-nucleotide polymorphisms within microRNAs can predispose someone to cancer. MicroRNAs have been shown to target both tumor suppressors, inhibiting cancer development, as well as oncogenes, stimulating cancer development. Some microRNAs can switch between these two functions and behave as a tumor suppressor at one time and an oncogene at another time. MicroRNAs can be used for diagnostic purposes as well as prognostic evaluations. Outside of microRNAs, ultraconserved genes, another group of non-coding RNAs, also express differently in cancer patients. Large intervening non-coding RNAs, specifically one termed HOTAIR, have been quantified in very high levels in cancer cells and have been implicated in metastasis. Further research into noncoding RNAs may allow for the development of therapies that will target non-coding RNAs creating better treatment options for cancer patients, improving their prognosis. This review discusses the most current discoveries about non-coding RNAs, revealing their associations with cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Over the past decade, non-coding RNA-based therapeutics have proven as a great potential for the development of targeted therapies for cancer and other diseases. The discovery of the critical function of microRNAs (miRNAs) has generated great excitement in developing miRNA-based therapies. The dysregulation of miRNAs contributes to the pathogenesis of various human diseases and cancers by modulating genes that are involved in critical cellular processes, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, drug resistance, and tumorigenesis. miRNA (miRNA mimic, anti-miRNA/antagomir) and small interfering RNA (siRNA) can inhibit the expression of any cancer-related genes/mRNAs with high specificity through RNA interference (RNAi), thus representing a remarkable therapeutic tool for targeted therapies and precision medicine. siRNA and miRNA-based therapies have entered clinical trials and recently three novel siRNA-based therapeutics were approved by the Food and Drug Administration (FDA), indicating the beginning of a new era of targeted therapeutics. The successful clinical applications of miRNA and siRNA therapeutics rely on safe and effective nanodelivery strategies for targeting tumor cells or tumor microenvironment. For this purpose, promising nanodelivery/nanoparticle-based approaches have been developed using a variety of molecules for systemic administration and improved tumor targeted delivery with reduced side effects. In this review, we present an overview of RNAi-based therapeutics, the major pharmaceutical challenges, and the perspectives for the development of promising delivery systems for clinical translation. We also highlight the passive and active tumor targeting nanodelivery strategies and primarily focus on the current applications of nanoparticle-based delivery formulations for tumor targeted RNAi molecules and their recent advances in clinical trials in human cancers. [ABSTRACT FROM AUTHOR]

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting messenger RNA (mRNA) transcripts. Recently, a miRNA expression profile of human tumors has been characterized by an overall miRNA downregulation. Explanations for this observation include a failure of miRNA post-transcriptional regulation, transcriptional silencing associated with hypermethylation of CpG island promoters and miRNA transcriptional repression by oncogenic factors. Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation. However, no loss-of-function genetic alterations in the genes encoding these proteins have been reported. Here we have identified truncating mutations in TARBP2 (TAR RNA-binding protein 2), encoding an integral component of a DICER1-containing complex, in sporadic and hereditary carcinomas with microsatellite instability. The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs. The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth. Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small, noncoding RNAs with important function in development, cell differentiation, and regulation of cell cycle and apoptosis. MiRNA expression is deregulated in cancer by a variety of mechanisms including amplification, deletion, mutation, and epigenetic silencing. Several studies have now shown that miRNAs are involved in the initiation and progression of cancer. in this review, briefly describe miRNA biogenesis and discuss how miRNAs can act:as oncogepes and tumor suppressors. We also address the role of miRNAs in the diagnosis, prognosis, and treatment of cancer. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a large family of short, single-stranded, highly conserved noncoding RNAs involved in gene regulation that can regulate gene expression through sequence-specific base pairing with target messenger RNAs (mRNAs). miRNAs have been implicated in the development of a wide variety of cancers as well as heart disease and other diseases. This review describes the role of miRNAs in human disease, methodology for evaluating miRNA gene expression, and the potential role of miRNAs as therapeutic agents and targets for the treatment of disease. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs), a novel class of small non-coding RNAs, are effective post-transcriptional regulators of gene expression, exhibiting, when altered in human tumors, both oncogenic and tumor suppressive potential. Recently, miRNA involvement in the pathophysiology of brain cancer has been assessed. Aberrant gene expression is the main mechanism of miRNAs dysfunction in cancer, with abnormal expression levels of mature and/or precursor miRNA expression in tumor samples versus normal. MiRNA germline and somatic mutations or polymorphisms in the protein coding messenger RNA targeted by miRNAs may also occur, contributing to cancer predisposition, initiation and/or progression. If present in somatic cells, miRNA alterations may play a role in tumor initiation, while if present in germ line cells they could constitute a cancer predisposing event. MiRNA expression profiling of human tumors has led to the identification of signatures correlated with the tumor diagnosis, staging, progression, prognosis and response to treatment. MiRNA fingerprinting can therefore be added to the diagnostic and prognostic tools used by medical oncologists. Furthermore, new therapeutic strategies involving miRNA silencing or miRNA mimics could be proposed based on the roles of these small non-coding RNAs as oncogenes and tumor suppressors in brain tumors. [ABSTRACT FROM AUTHOR]