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MiR-155 is a
microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
that in humans is encoded by the ''MIR155'' host
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
or ''MIR155HG''. MiR-155 plays a role in various
physiological Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...
and
pathological Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
processes.
Exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It is the opposite of endogeneity or endogeny, the fact of being influenced from within a system. Economics In an economic model, an ...
molecular control ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'' of miR-155 expression may inhibit
malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
growth, viral infections, and enhance the progression of
cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
diseases.


Discovery

The ''MIR155HG'' was initially identified as a
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that was transcriptionally activated by promoter insertion at a common retroviral integration site in
B-cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
lymphomas Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
and was formerly called BIC (B-cell Integration Cluster). The ''MIR155HG'' is transcribed by
RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a Protein complex, multiprotein complex that Transcription (biology), transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNA pol ...
and the resulting ~1,500
nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
is
capped In sport, a cap is a player's appearance in a game at international level. The term dates from the practice in the United Kingdom of awarding a cap to every player in an international match of rugby football and association football. In the e ...
and polyadenylated. The 23 nucleotide single-stranded miR-155, which is harbored in
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
3, is subsequently processed from the parent RNA molecule.


Biogenesis

The MIR155HG RNA transcript does not contain a long
open reading frame In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames ...
(ORF), however, it does include an imperfectly base-paired stem loop that is conserved across species. This non-coding RNA (
ncRNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-co ...
) is now defined as a primary-miRNA (pri-miRNA). Once miR-155 pri-miRNA is transcribed, this transcript is cleaved by the nuclear
microprocessor complex The microprocessor complex is a protein complex involved in the early stages of processing microRNA (miRNA) and RNA interference (RNAi) in animal cells. The complex is minimally composed of the ribonuclease enzyme Drosha and the dimeric RNA-bin ...
, of which the core components are the RNase III type endonuclease
Drosha Drosha is a Class 2 ribonuclease III enzyme that in humans is encoded by the ''DROSHA'' (formerly ''RNASEN'') gene. It is the primary nuclease that executes the initiation step of miRNA processing in the nucleus. It works closely with DGCR8 and ...
and the DiGeorge critical region 8 ( DGCR8) protein, to produce a 65 nucleotide
stem-loop Stem-loops are nucleic acid Biomolecular structure, secondary structural elements which form via intramolecular base pairing in single-stranded DNA or RNA. They are also referred to as hairpins or hairpin loops. A stem-loop occurs when two regi ...
precursor miRNA (pre-mir-155) (see Figure 2). Following export from the nucleus by
exportin-5 Exportin-5 (XPO5) is a protein that, in humans, is encoded by the ''XPO5'' gene. In Eukaryote, eukaryotic cells, the primary purpose of XPO5 is to export MicroRNA, pre-microRNA (also known as pre-miRNA) out of the Cell nucleus, nucleus and into the ...
, pre-mir-155 molecules are cleaved near the terminal loop by
Dicer Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into shor ...
resulting in RNA duplexes of ~22nucleotides. Following Dicer cleavage, an
Argonaute The Argonaute protein family, first discovered for its evolutionarily conserved stem cell function, plays a central role in RNA silencing processes as essential components of the RNA-induced silencing complex (RISC). RISC is responsible for the ...
(Ago) protein binds to the short RNA duplexes, forming the core of a multi-subunit complex called the RNA-induced silencing complex (
RISC In electronics and computer science, a reduced instruction set computer (RISC) is a computer architecture designed to simplify the individual instructions given to the computer to accomplish tasks. Compared to the instructions given to a comp ...
). In a manner similar to
siRNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded non-coding RNA molecules, typically 20–24 base pairs in length, similar to microRNA (miRNA), and operating within the RN ...
duplexes, one of the two strands, the "passenger miRNA" (miR-155*), is released and degraded while the other strand, designated the "guide strand" or "mature miRNA" (miR-155), is retained within the RISC. Recent data suggest that both arms of the pre-miRNA hairpin can give rise to mature miRNAs. Due to the increasing number of examples where two functional mature miRNAs are processed from opposite arms of the same pre-miRNA, pre-mir-155 products are now denoted with the suffix -5p (from the 5′ arm) (e.g. miR-155-5p) and -3p (from the 3′ arm) (e.g. miR-155-3p) following their name (see Figure 3). Once miR-155-5p/-3p is assembled into the RISC, these molecules subsequently recognize their target messenger RNA (
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
) by base pairing interactions between nucleotides 2 and 8 of miR-155-5p/-3p (the seed region) and
complementary Complement may refer to: The arts * Complement (music), an interval that, when added to another, spans an octave ** Aggregate complementation, the separation of pitch-class collections into complementary sets * Complementary color, in the visu ...
nucleotides predominantly in the 3′-untranslated region ( 3′-UTR) of mRNAs (see Figure 4 and 5 below). Finally, with the miR-155-5p/-3p acting as an adaptor for the RISC, complex-bound mRNAs are subjected to translational repression (i.e. inhibition of
translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
initiation) and/or degradation following
deadenylation Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...
.


Evolutionary conservation

Early
phylogenetic In biology, phylogenetics () is the study of the evolutionary history of life using observable characteristics of organisms (or genes), which is known as phylogenetic inference. It infers the relationship among organisms based on empirical dat ...
analyses demonstrated that the sequence of pre-mir-155 and miR-155-5p was conserved between human, mouse, and chicken. Recent annotated sequencing data found that 22 different organisms including, mammals, amphibians, birds, reptiles, sea squirts, and sea lampreys, express a conserved miR-155-5

Currently much less sequence data is available regarding miR-155-3p, therefore, it is not clear how conserved this miRNA is across specie


Tissue distribution

Northern blot The northern blot, or RNA blot,Gilbert, S. F. (2000) Developmental Biology, 6th Ed. Sunderland MA, Sinauer Associates. is a technique used in molecular biology research to study gene expression by detection of RNA (or isolated mRNA) in a sample.Ke ...
analysis found that miR-155 pri-miRNA was abundantly expressed in the human spleen and thymus and detectable in the liver, lung, and kidney. Sequence analysis of small RNA clone libraries comparing miRNA expression to all other organ systems examined established that miR-155-5p was one of five miRNAs (i.e. miR-142, miR-144, miR-150, miR-155, and miR-223) that was specific for hematopoietic cells including
B-cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
,
T-cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
,
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
and
granulocytes Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that ...
. Together these results suggest that miR-155-5p is expressed in a number of tissues and cell types and, therefore, may play a critical role in a wide variety of biological processes, including
hematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
Although very few studies have investigated the expression levels of miR-155-3p, Landgraf et al. established that expression levels of this miRNA was very low in hematopoietic cells. Additionally, PCR analyses found that while miR-155-3p was detectable in a number of human tissues the expression levels of this miRNA were 20–200 fold less when compared to miR-155-5p levels. Even though the function of miR-155-3p has been largely ignored, several studies now suggest that, in some cases (
astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s and
plasmacytoid dendritic cell Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. T ...
s), both miR-155-5p and -3p can be functionally matured from pre-mir-155.


Targets

Bioinformatic Bioinformatics () is an interdisciplinary field of science Science is a systematic discipline that builds and organises knowledge in the form of testable hypotheses and predictions about the universe. Modern science is typically divi ...
analysis using TargetScan 6.2 (release date June, 2012

revealed at least 4,174 putative human miR-155-5p mRNA targets exist, with a total of 918 conserved sites (i.e. between mouse and human) and 4,249 poorly conserved sites (i.e. human only). Although the TargetScan 6.2 algorithm cannot be utilized to determine the miR-155-3p putative targets, one would speculate that this miRNA may also potentially regulate the expression of thousands of mRNA targets. A comprehensive list of miR-155-5p/mRNA targets that were experimentally authenticated by both the demonstration of endogenous transcript regulation by miR-155-5p and validation of the miR-155-5p seed sequence through a reporter assay was recently assembled. This list included 140 genes and included regulatory proteins for myelopoiesis and leukemogenesis (e.g. SHIP-1, AICDA,
ETS1 Protein C-ets-1 is a protein that in humans is encoded by the ''ETS1'' gene. The protein encoded by this gene belongs to the ETS family of transcription factors. Function There are 28 ETS genes in humans and 27 in mice. They bind the DNA via ...
, JARID2, SPI1, etc.), inflammation (e.g.
BACH1 Transcription regulator protein BACH1 is a protein that in humans is encoded by the ''BACH1'' gene. Function This gene encodes a transcription factor that belongs to the cap'n'collar type of basic region leucine zipper factor family (CNC-bZip) ...
,
FADD FAS-associated death domain protein, also called MORT1, is encoded by the ''FADD'' gene on the 11q13.3 region of chromosome 11 in humans. FADD is an Signal transducing adaptor protein, adaptor protein that bridges members of the Tumor necrosi ...
,
IKBKE Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the ''IKBKE'' gene. Interactions IKBKE has been shown to interact with TANK. Function ...
, INPP5D,
MYD88 Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the ''MYD88'' gene. originally discovered in the laboratory of Dan A. Liebermann (Lord et al. Oncogene 1990) as a Myeloid differentiation primary resp ...
,
RIPK1 Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis, necroptosis, and PANoptosis Some of th ...
, SPI1,
SOCS SOCS (suppressor of cytokine signaling proteins) refers to a family of genes involved in inhibiting the JAK-STAT signaling pathway. Genes * CISH (gene), CISH * SOCS1 * SOCS2 * SOCS3 * SOCS4 * SOCS5 * SOCS6 * SOCS7 Structure All SOCS have certai ...
, etc.) and known
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
s (e.g. CEBPβ, IL17RB, PCCD4, TCF12, ZNF652, etc.). The validated miR-155-5p binding site harbored in the SPI1 mRNA and the validated miR-155-3p binding site harbored in the IRAK3 mRNA are shown in Figures 4 and 5 respectively.


Physiological roles


Hematopoiesis

Hematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
is defined as the formation and development of blood cells, all of which are derived from hematopoietic stem-progenitor cells (HSPCs). HSPCs are primitive cells capable of self-renewal and initially differentiate into
common myeloid progenitor CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocyt ...
(CMP) or
common lymphoid progenitor Lymphopoiesis (lĭm'fō-poi-ē'sĭs) (or lymphocytopoiesis) is the generation of lymphocytes, one of the five types of white blood cells (WBCs). It is more formally known as lymphoid hematopoiesis. Disruption in lymphopoiesis can lead to a number ...
(CLP) cells. CMPs represent the cellular population that has become myeloid lineage and it is the point that
myelopoiesis In hematology, myelopoiesis in the broadest sense of the term is the production of bone marrow and of all cells that arise from it, namely, all blood cells. In a narrower sense, myelopoiesis also refers specifically to the regulated formation of ...
begins. During myelopoiesis further cellular differentiation takes place including
thrombopoiesis Thrombopoiesis is the formation of thrombocytes (blood platelets) in the bone marrow. Thrombopoietin is the main regulator of thrombopoiesis. Thrombopoietin affects most aspects of the production of platelets. This includes self-renewal and expa ...
,
erythropoiesis Erythropoiesis (from Greek ''erythro'', meaning ''red'' and ''poiesis'', meaning ''to make'') is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is s ...
,
granulopoiesis Granulopoiesis (or granulocytopoiesis) is a part of haematopoiesis, that leads to the production of granulocytes. A granulocyte, also referred to as a polymorphonuclear leukocyte (PMN), is a type of white blood cell that has multi lobed nuclei, u ...
, and monocytopoiesis. CLPs subsequently differentiate into
B-cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
and
T-cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
in a process designated
lymphopoiesis Lymphopoiesis (lĭm'fō-poi-ē'sĭs) (or lymphocytopoiesis) is the generation of lymphocytes, one of the five types of white blood cells (WBCs). It is more formally known as lymphoid hematopoiesis. Disruption in lymphopoiesis can lead to a number ...
. Given that miR-155-5p is expressed in hematopoietic cells it was hypothesized that this miRNA plays a critical role in these cellular differentiation processes. In support of this premise, miR-155-5p was found to be expressed in CD34(+) human HSPCs, and it was speculated that this miRNA may hold these cells at an early stem-progenitor stage, inhibiting their differentiation into a more mature cell (i.e. megakaryocytic/erythroid/granulocytic/monocytic/B-lymphoid/T-lymphoid). This hypothesis was substantiated when pre-mir-155 transduced HSPCs generated 5-fold fewer myeloid and 3-fold fewer erythroid colonies. Additionally, Hu et al. demonstrated that the homeobox protein,
HOXA9 Homeobox protein Hox-A9 is a protein that in humans is encoded by the ''HOXA9'' gene. In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromos ...
, regulated ''MIR155HG'' expression in myeloid cells and that this miRNA played a functional role in hematopoiesis. These investigators found that forced expression of miR-155-5p in bone marrow cells resulted in a ~50% decrease in SPI1 (i.e. PU.1), a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
and a regulator of myelopoiesis, and a validated target of this miRNA. It was also established that ''in vitro'' differentiation of purified human erythroid progenitor cells resulted in a progressive decrease of miR-155-5p expression in mature red cells. Additionally, mice deficient in pre-mir-155 showed clear defects in lymphocyte development and generation of B- and T-cell responses ''in vivo''. Finally, it was established that regulatory T-cell ( Tregs) development required miR-155-5p and this miRNA was shown to play a role in Treg homeostasis and overall survival by directly targeting
SOCS1 Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the ''SOCS1'' gene. ''SOCS1'' orthologs have been identified in several mammals for which complete genome data are available. Function This gene encodes a member of t ...
, a negative regulator for
IL-2 The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...
signaling. Taken together, these results strongly suggest that miR-155-5p is an essential molecule in the control of several aspects of hematopoiesis including myelopoiesis, erythropoiesis, and lymphopoiesis.


Immune system

The
innate immune system The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...
constitutes the first line of defense against invading
pathogens In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ. The term ...
and is regarded as the major initiator of inflammatory responses. Its cellular component involves primarily
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
/
macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
,
granulocytes Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that ...
, and
dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
(DCs), which are activated upon sensing of conserved pathogen structures (
PAMPs Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes, but not present in the host. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both p ...
) by pattern recognition receptors such as
Toll-like receptors Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...
((TLRs)). ''MIR155HG'' (i.e. miR-155-5p) expression is greatly enhanced by TLR agonist stimulation of macrophages and dendritic cells. Since microbial
lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...
(an agonist of
TLR4 Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approx ...
) activates a chain of events that lead to the stimulation of the
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
and AP-1 transcription factors, it was hypothesized that
endotoxin Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...
activation of ''MIR155HG'' may be mediated by those transcription factors. Indeed, ''MIR155HG'' expression was found to be activated in LPS treated murine macrophage cells (i.e. Raw264.7) by an NF-κB-mediated mechanism. Furthermore, '' H. pylori'' infection of primary murine bone marrow-derived macrophages resulted in a NF-κB dependent up-regulation of ''MIR155HG''. In the context of viral infection
vesicular stomatitis virus ''Indiana vesiculovirus'', formerly ''Vesicular stomatitis Indiana virus'' (VSIV or VSV) is a virus in the family ''Rhabdoviridae''; the well-known '' Rabies lyssavirus'' belongs to the same family. VSIV can infect insects, cattle, horses and pig ...
(VSV) challenge of murine peritoneal macrophages was reported to result in miR-155-5p over-expression via a retinoic acid-inducible gene I/JNK/NF-κB–dependent pathway. Support for a role of AP-1 in ''MIR155HG'' activation comes from studies using stimuli relevant to viral infection such as TLR3 ligand poly(I:C) or
interferon beta The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T cell, T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p2 ...
(IFN-β). Downstream of those stimuli AP-1 seems to play a major role in ''MIR155HG'' activation. Upon its initiation via activation of e.g. TLRs by pathogen stimuli miR-155-5p functions as a post-transcriptional regulator of innate immune signaling pathways. Importantly, miR-155-5p displays a similar responsiveness to pathogen stimuli (e.g. TLR4 agonist LPS) as major pro-inflammatory marker mRNAs. Once activated, miR-155-5p suppresses negative regulators of inflammation. These include inositol polyphosphate-5-phosphatase (INPP5D also denoted SHIP1) and
suppressor of cytokine signaling 1 Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the ''SOCS1'' gene. ''SOCS1'' orthologs have been identified in several mammals for which complete genome data are available. Function This gene encodes a member of t ...
(SOCS1), suppression of which promotes cell survival, growth, migration, and anti-pathogen responses. Besides supporting the activation of defense pathways miR-155-5p may also limit the strength of the resulting NF-κB dependent inflammatory response, suggesting varying functions of miR-155 at different stages of inflammation. Taken together, these observations imply that the activation of the ''MIR155HG'' may be context-dependent given that both AP-1- and NF-κB-mediated mechanisms regulate the expression of this gene. These studies also suggest that a broad range of viral and bacterial inflammatory mediators can stimulate the expression of miR-155-5p and indicate that there is an intimate relationship between inflammation, innate immunity and ''MIR155HG'' expression.


Activity and phenotypes

There is evidence that miR-155 participates in cascades associated with
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
s and hypertension, and was also found to be implicated in immunity,
genomic instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneu ...
, cell differentiation, inflammation, virus associated infections, cancer, and
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
. Protective roles of miR-155 may arise in response to its action on silencing genes thereby regulating their expression time,
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in miR-155 target site deny it the optimal access necessary to bring about gene silencing, leading to over abundance of delinquent activities that may go
malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
, for example, miR-155 role as a protective agent against predisposition to B Cell associated malignancies is emphasized by maintaining the balance of Activation-Induced Cytidine Deaminase (
AID In international relations, aid (also known as international aid, overseas aid, foreign aid, economic aid or foreign assistance) is – from the perspective of governments – a voluntary transfer of resources from one country to another. Th ...
) enzyme. MiR-155 mediates regulation of AID abundance and expression time upon immunological cues however, mutations in the target on AID mRNA result in its unresponsiveness to miR-155 silencing and lead to unbridled expression of its protein causing wild immature B-lymphocyte surges and AID-mediated
chromosomal translocation In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes "balanced" and "unbalanced" translocation, with three main types: "reciprocal", "nonreciprocal" and "Robertsonian" transloc ...
s.


Clinical significance


Cardiovascular

Transfection of miR-155 into human primary lung fibroblasts reduces the endogenous expression of the
angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...
receptor AT1R protein. Furthermore, AT1R mediates angiotensin II-related elevation in blood pressure and contributes to the pathogenesis of heart failure. Defective miR-155 function could be implicated in
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
and cardiovascular diseases if the cis-regulatory site on 3` UTR of AT1R (miR-155 target site) was affected due to a SNP polymorphism in AT1R itself. This mutation is disruptive of miR-155 targeting and thus preventive of AT1R expression down-regulation. In low blood pressure over-expression of miR-155 correlates with the impairment of AT1R activity.


Immunity

miR-155 is involved in immunity by playing key roles in modulating humoral and innate cell-mediated immune responses, for example, In miR-155 deficient mice, immunological-memory is impaired; making it fall prey to repetitive bouts of invasions by the same pathogen (Rodriguez et al. 2007), maturation and specificity of miR-155-deficient B-lymphocytes are impaired since the process relies on AID enzyme which has a miR-155 target in its 3′ UTR end. The phenotypic consequences involving deficiency of miR-155 in mice show later in life where the animals develop lung and intestinal
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...
s. Activated B and T cells show increased miR-155 expression, the same goes for
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s and
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s of the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
. MiR-155 is crucial for proper lymphocyte development and maturation. Details of various manifestations of miR-155 levels and involvement in activities that ascertain optimal immune responses have been the subject of many researches:


Reduction of IgG1

Defective T and B cells as well as markedly decreased
IgG1 Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ant ...
responses were observed in miR-155-deficient mice, IgG1 is reduced whereas the expression of the
IgM Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also ...
immunoglobulin remains normal in these mice. The change in IgG1 levels maybe explained by the fact that it is a target for miR-155 in B cells, the protein-encoding mRNA for the transcriptional regulator Pu.1-protein, elevation of Pu.1 protein predisposes defective IgG1 production. In addition to Pu.1, there are nearly 60 other differentially elevated genes in miR-155 deficient B cells, further inspection revealed possible miR-155 target sites in the 3′ UTR regions in these genes.


Lymphocyte malignancies

Mature receptors
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
and specificity of lymphocytes to pathogenic agents underlie proper immune responses, optimal miR-155 coordination is required for manufacturing of normal B lymphocytes, production of high-affinity antibodies and balancing of BCR signalling. It has been demonstrated that miR-155 can be transferred through gap junctions from leukemic cells to healthy B cells and promote their transformation to tumorigenic-like cells. Selection of competent B cells takes place in the
germinal center Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
where they are trained to differentiate body cells vs. foreign antigens, they compete for antigen recognition and for T cell help, in this fashion of selective pressure those B Cells that demonstrated high-affinity receptors and cooperation with T cells (
affinity maturation In immunology, affinity maturation is the process by which TFH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce ...
) are recruited and deployed to the bone marrow or become memory B cells, apoptotic termination takes place for those B Cells failing the competition. Immature B cells which are miR-155 deficient evade apoptosis as a result of elevated Bcl-2 protein levels; a protein that was found to be involved in B Cell malignancies and to be controlled by miR-155.


Inflammation

Inflammatory responses to triggers such as
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
involve macrophages with components that include miR-155. miR-155 is overexpressed in atopic dermatitis and contributes to chronic skin inflammation by increasing the proliferative response of T(H) cells through the downregulation of CTLA-4. In
Autoimmune disorders An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
such as rheumatoid arthritis, miR-155 showed higher expression in patients' tissues and synovial fibroblasts. In multiple sclerosis, increased expression of mir-155 has also been measured in peripheral and CNS-resident myeloid cells, including circulating blood monocytes and activated microglia. It was also found that mir-155 is implicated in inflammation. Overexpression of mir-155 will lead to chronic inflammatory state in human.


DNA viruses

In
DNA virus A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and t ...
es, miRNAs were experimentally verified, miRNAs in viruses are encoded by dsDNAs, examples of such viruses include herpesviruses such as Humans-Epstein-Barr Virus ( EBV) and
adenoviruses Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from the ...
, another virus expressing miR-155-like miRNA in chickens is the oncogenic MDV-1 whose non-oncogenic relative MDV-2 does not, this suggests implication of miR-155 in lymphomagenesis. Viruses can exploit host miRNAs to the degree that they use host miRNAs to encode for viral clones for example: miR-K12-11 in Kaposi's-sarcoma-associated Herpesvirus has a target specificity region
orthologous Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
to that of miR-155's; mimicking the action of miR-155 and, sharing targets with it, thus it can be thought to suppress miR-155 accessibility to its targets by competition and this in effect downregulates expression of genes playing roles in cellular growth and apoptosis in a manner that defies regulations by miR-155. EBV modulates host miR-155 expression, which is essential for growth of EBV-infected B cells. EBV-infected cells have increased expression of miR-155 thereby disturbing equilibrium of expression for genes regulating transcription in those cells.


Cancer

Over-silencing by miR-155 may result in triggering oncogenic cascades that begin by apoptotic resistance, the pro-apoptotic Tumour Protein-53-induced-nuclear-protein1 ( TP53INP1) is silenced by miR-155, over-expression of miR-155 leads to decreased levels of TP53INP1 in pancreatic ductal
adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ; AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
s and possibly in other epithelial cancers where TP53INP1 activity is lost thereby resulting in apoptosis evasion and uncontrolled bouts of growth. Inactivation of DNA Mismatch Repair ( MMR) as identified by elevation of mutation rates is the cause of
Lynch Syndrome Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon ...
(LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), down-regulation of MMR controlling protein is carried out by over-expression of miR-155, MMR is controlled by a group of conserved proteins, reduced activity of these proteins results in elevated levels of mutations in the phenotype triggering a march towards developing this type of cancer. Other types of tumors in which miR-155 over-expression was reported include: thyroid carcinoma, breast cancer, colon cancer, cervical cancer, and lung cancer, where distinct miR-155 expression profiles quantification can potentially serve as signals for tumor detection and evaluation of prognosis outcome. It is shown in an analysis that miR-155 expression is associated with survival in triple negative breast cancer.


Notes


See also

*
MicroRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...


References


External links


miRBase

miRBase entries for all known mir-155
* {{miRNA precursor families MicroRNA Non-coding RNA