MicroRNA - Volume 2, Issue 3, 2013

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. The accumulation of mature CD5(+) B-lymphocytes in bone marrow, peripheral blood, and lymphoid organs due to decreased apoptosis is a characteristic of this malignancy. MicroRNAs (miRNAs) are small noncoding RNAs able to regulate the expression of many target genes, including the main apoptosis regulators BCL2 and MCL1. miRNAs play key roles in the pathogenesis of CLL, including specific miRNAs located at the 13q14 chromosomal region that is often deleted or mutated in patients with CLL. In this paper, we review new investigations that underscore the significance of miRNAs for CLL pathogenesis.

Plasma cell dyscrasias are a group of related disorders that have in common the clonal proliferation of plasma cells with resultant production of a monoclonal immunoglobulin that can be detected on serum protein electrophoresis (M-spike). This term incorporates the Plasma Cell Neoplasms along with other related disorders that are not considered malignant. Comprehensive genomic studies have greatly advanced our understanding of the genetic complexity of these diseases in recent years, however they continue to be considered incurable with a highly heterogeneous phenotype. It is clear that a deeper level of knowledge of the biological events underlying the development of these diseases is needed to identify new targets and generate effective novel therapies. MicroRNAs (miRNAs), which are single strand, 20- nucleotide, non-coding RNAs, are key regulators of gene expression and have been reported to exert transcriptional control in multiple myeloma and other plasma cell dyscrasias. miRNAs are now recognized to play a role in many key areas such as cellular proliferation, differentiation, apoptosis and stress response. Substantial advances have been made in recent years in terms of our understanding of the biological role of miRNAs in this complex and diverse set of disorders, leading to the new information, which is of diagnostic and prognostic relevance.

The myelodysplastic syndromes (MDS) are heterogeneous clonal disorders of ineffective hematopoiesis characterized by limited treatment options and a poor prognosis. These poor clinical characteristics stem from a poor understanding of the molecular abnormalities that drive disease pathogenesis. MicroRNAs (miRNAs) have recently been described to play wide-ranging roles in normal and malignant hematopoiesis, but very few miRNAs have been shown to be consistently dysregulated in MDS. Even fewer candidate disease miRNAs have undergone functional validation, and the clinical relevance of these miRNAs remains to be determined. Despite the fact that MDS has been shown to be a disease initiated in hematopoietic stem cells (HSC), most existing studies examining miRNA expression in MDS have used unfractionated or only partially purified bone marrow (BM) cell populations, likely explaining in part the limited insight that provided by these studies. A more robust characterization of purified disease -initiating cell populations followed by rigorous functional validation using in vivo disease models will be vital to identifying dysregulated miRNAs of functional significance in MDS. Such studies promise to provide key insights into disease pathogenesis and potentially open new avenues towards the development of therapies targeting miRNAs themselves or the pathways that they regulate.

Aicardi Goutieres Syndrome (AGS) is characterized by mutations occurring in genes encoding RNAses. AGS mutations silence intracellular RNases resulting in an intracellular overload of short RNAs arresting the physiological production of microRNA required for brain development. MiR-219 is typically down-regulated in Aicardi Goutieres Syn-drome (AGS). The goal of this study is to investigate miR-219 role in protecting astrocytes co-cultured with AGS-mutated lymphocytes. These lymphocytes display neurotoxic properties due to the presence of AGS-mutation and to their activa-tion by interpheron-alpha (IFN). Obtained results provide the evidence that astrocytes transfected with microRNA-219 are protected from the neurotoxic action of AGS lymphocytes activated by IFN-alpha. In particular, the miR-219 transfection increased astrocyte viability, growth, and differentiation while decreasing cell necrosis and apoptosis. Thus, microRNA-219 transfection is a valuable strategy in order to confer resistance to astrocytes towards lymphocyte-induced neurotoxici-ty especially in the presence of IFN-alpha, whose levels are typically increased in the cerebrospinal fluid of AGS patients.

Tumor-derived vesicles (TDV) have been recently implicated in immunosuppression by transporting specific proteins, including Fas ligand (FasL) and TRAIL, to immune cells. We hypothesized that TDVs carrying miRNAs with immunological function could interfere with the translational machinery of immune cells and lead to TDV-mediated immunosuppression in cancer. We show that TDVs from human tumor cells indeed contain multiple miRNA species with known roles in lymphocyte development and function: hsa-miR-146a, miR-29a, and miR-21. Quantification by RT-PCR shows that the amount of miR-21 within TDVs isolated from the breast cancer cell line HCC1806 is at physiologically relevant levels. Additionally, we show that these miRNAs carried by TDVs copurify with argonaute proteins. This observation corroborates the idea that the machinery of microvesicle secretion and that of RNA interference are interconnected.

The pathogenesis of atherosclerosis involves the interplay of inflammation, altered cellular activity, angiogenesis, and neointima formation. The main cellular participants in atherosclerosis include vascular endothelial cells, smooth muscle cells, and monocytes. The recent discovery of small, non-coding RNAs, microRNAs (miRNAs), and their influence on these processes has provided a greater molecular insight into atherosclerosis. This in turn has led to increase focus on the potential utility of miRNA subtypes as biomarkers for coronary artery disease. Furthermore miRNAs could potentially provide therapeutic targets for the treatment of atherosclerosis and its complications. In this review, we discuss the experimental and clinical evidence for the role of miRNAs in the pathogenesis of coronary artery disease, the limitations of the data and challenges facing the field.

The presence of microRNAs (miRNAs) and their ease of detection in body fluids including serum and whole blood have opened new avenues for developing novel non-invasive methods for diagnostics and therapeutic applications for both infectious and noninfectious diseases. Blood-borne infectious viral diseases pose challenge to public health at large and, especially to health care workers, emergency responders and public safety personnel. Several studies have explored these newly identified miRNAs in blood borne infectious diseases for various purposes. This review highlights and focuses only on some of the available literature on the patient associated cellular miRNAs in blood-borne viral diseases and its occasional extrapolation to infected cell cultures as it relates to blood-borne hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV). Where appropriate, this review further points to the potential of miRNAs as non-invasive early disease detection biomarkers for these viral infections as well as possible prospects and challenges of miRNA-based therapies in treating these viral infections.

MicroRNAs are small non-coding RNAs, 19-24 nucleotides in length that bind to the 3'UTR of target mRNAs and thus regulate gene expression post transcriptionally. MiRNAs have been implicated in various biological and pathological processes. The binding of miRNAs to 3'UTR is crucial for regulating the mRNA level and hence protein expression. The complementarity between the miRNA and its target mRNA is critical for the outcome of the miRNA mediated translational regulation. Changes in the nucleotide sequence of either the miRNA or its target binding site can deregulate gene expression and hence lead to the development of various pathological conditions, including tumorigenesis. To determine whether sequence alterations in miRNA genes and their target sites in mRNAs are associated with the colorectal cancers, we screened two miRNA genes—Let-7c, mir-206 and selected miRNA binding regions on KRAS, TP53 and GJA1 3'UTR. This study was carried out on 60 human colorectal cancer tissue samples. Our sequencing results did not reveal any mutation/single-nucleotide polymorphism in either the miRNAs or the miRNA binding sites in any of the tumor samples. This data suggests that mutations/SNPs targeting miRNA genes or their binding sites in 3'-untranslated regions are infrequent events in the development of colorectal cancer in Kashmiri population.

Leishmaniasis represents endemic infections that occur predominantly, in tropical and sub-tropical regions. The current situation for the chemotherapy of leishmaniasis is more promising than it has been for several decades with both new drugs and new formulations of old drugs either recently approved or in clinical trials. Investigations focused on parasite biology and identification of novel drug targets have become of great importance. The identification and characterization of microRNA (miRNAs) in the parasite and their possible biological action hopefully facilitate the discovery of potential antiparasitic drug targets against leishmaniasis. microRNA and other small RNA transcripts are derived from distinct loci in the genome and play critical roles in RNA–mediated gene silencing mechanisms in the organisms. miRNAs regulate mRNA stability through perfect and imperfect match to the targets. The biological activities of miRNAs have been related to many biological events, from resistant to microbe infections to cellular differentiation. miRNA like-elements have been identified in Leishmania major. Identification of miRNA-like elements in L. major provides a foundation for subsequent functional studies. Computational strategies provide an efficient manner to predict miRNA genes and their targets. Twenty-five potential miRNA-like elements in different chromosomes (chr.) like chr. 7th, 8th, 17th, 18th, 21st, 23rd, 25th, 26th, 29th, 31st, 32nd, 33rd, 34th and 35th of L. major have been identified. It is known from this study that the target genes of miRNA-like elements involve multidrug resistant protein such as ABC transporter, ribosomal protein, RNA binding proteins, hydrolase and exonuclease.