Mir-223
Encyclopedia
In molecular biology MicroRNA-223 (miR-223) is a short RNA
molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. miR-223 is a hematopoietic specific microRNA with crucial functions in myeloid
lineage development. It plays an essential role in promoting granulocytic
differentiation while also being associated with the suppression of erythrocytic differentiation. miR-223 is commonly repressed in hepatocellular carcinoma
and leukemia
. Higher expression levels of miRNA-223 are associated with extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the stomach
and recurrent ovarian cancer
. In some cancers the microRNA-223 down-regulation is correlated with higher tumor burden, disease aggressiveness, and poor prognostic factors. MicroRNA-223 is also associated with rheumatoid arthritis
, sepsis
, type 2 diabetes, and hepatic ischemia
.
proteins which are myeloid transcription factors.
MicroRNA-223 selectively targets distinct populations of transcripts harboring AU-rich element
s. More specifically, it was validated that the RhoB
mRNA is a bona fide miR-223 target. miR-223 also regulates cyclin E
activity by modulating expression of the FBXW7
protein. In particular, overexpression of miR-223 reduces FBXW7 mRNA levels while increasing endogenous cyclin E protein and activity levels.
miR-223 acts as fine-tuner of granulocytic differentiation, maturation, and function. More specifically, human granulocytic differentiation is controlled by a regulatory circuitry involving miR-223 and two transcriptional factors, NFIA
and C/EBPα
. These two factors compete for binding: NFI-A maintains miR-223 at low levels whereas C/EBPα upregulates miR-223 expression. The competition by C/EBPα and the granulocytic differentiation are favored by a negative-feedback loop in which miR-223 represses NFI-A translation.
Analysis of expression profiles indicate that miR-223 expression decreases as cells mature during monocytic, erythroid, and mast cell
differentiation. miR-223 down-regulation during erythropoiesis is required for erythrocyte proliferation and differentiation at progenitor and precursor level. This down-modulation promotes erythropoiesis favoring translation of the key functional protein LMO2
resulting in reversible regulation of erythroid and megakaryocytic differentiation.
MicroRNA-223 also plays an essential role during osteoclast
differentiation. More specifically, miR-223 expression suppresses the differentiation of osteoclast precursors into osteoclast thus making it a potential viable therapeutic target for a range of bone metabolic disorders with excess osteoclast activity.
, chronic lymphocytic leukemia
, acute lymphoblastic leukemia
, acute myeloid leukemia
, gastric MALT lymphoma
, and recurrent ovarian cancer
.
Integrative analysis in hepatocellular carcinoma implicates Stathmin 1 (STMN1) as a downstream target of miR-223. Furthermore, miR-223 could suppress the luciferase activity in reporter construct containing the STMN1 3' untranslated region. The reduced expressions of miR-223 may predispose to the development of hepatocellular carcinoma via the widespread induction of chromosomal instability by STMN1.
MicroRNA-223 blocks the translation of E2F1
leading to inhibition of cell-cycle progression followed by myeloid differentiation. In acute myeloid leukemia (AML), miR-223 is down-regulated thus leading to E2F1 overexpression. The overexpressed E2F1 could bind to the miR-223 promoter and in turn lead to a further decrease in miR-223 expression through a negative feedback loop followed by myeloid cell-cycle progression at the expense of differentiation. Overexpression of E2F1 has been shown to be an oncogenic event that predisposes cells to transformation. While there is some indication of the miR-223 role in AML there is still little known about this microRNA function in chronic lymphocytic and acute lymphoblastic leukemia. Nevertheless, MicroRNA-223 expression levels decreased significantly with the progression of these two diseases thus associating miR-223 down-regulation with higher tumor burden, disease aggressiveness, and poor prognostic factors.
Gastric MALT lymphoma and recurrent ovarian cancer are associated with higher levels of MicroRNA-223 expression making them a potential biomarker.
patients suggesting that its expression in this cell type could contribute to the etiology of the disease.
(SIRS) patients and/or healthy controls. This suggests that miR-223 can be used as a biomarker for distinguishing sepsis from SIRS.
. This effect was associated with miR-223 role in Glut4
regulation and glucose metabolism.
, ephrin A1
, and ras homolog gene family member B
were predicted to be downstream targets of miR-223.
Non-coding RNA
A non-coding RNA is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA , non-messenger RNA and functional RNA . The term small RNA is often used for short bacterial ncRNAs...
molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. miR-223 is a hematopoietic specific microRNA with crucial functions in myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
lineage development. It plays an essential role in promoting granulocytic
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
differentiation while also being associated with the suppression of erythrocytic differentiation. miR-223 is commonly repressed in hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
and leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
. Higher expression levels of miRNA-223 are associated with extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the stomach
MALT lymphoma
MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue , frequently of the stomach, but virtually any mucosal site can be afflicted...
and recurrent ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
. In some cancers the microRNA-223 down-regulation is correlated with higher tumor burden, disease aggressiveness, and poor prognostic factors. MicroRNA-223 is also associated with rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
, type 2 diabetes, and hepatic ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
.
Characterization
MicroRNA-223 was initially identified bioinformatically and it was subsequently characterized as part of the haematopoietic system. Its gene resembles a myeloid gene and it could be driven by the PU.1 and C/EBPαCcaat-enhancer-binding proteins
CCAAT-enhancer-binding proteins are a family of transcription factors, composed of six members called C/EBP α to C/EBP ζ. They promote the expression of certain genes through interaction with their promoter. Once bound to DNA, C/EBPs can recruit so-called coactivators CCAAT-enhancer-binding...
proteins which are myeloid transcription factors.
MicroRNA-223 selectively targets distinct populations of transcripts harboring AU-rich element
AU-rich element
AU-rich elements are one of the most common types of regulatory elements found in mRNAs. They are involved in the control of gene expression. They are the most common determinant of RNA stability in mammalian cells....
s. More specifically, it was validated that the RhoB
RHOB
Ras homolog gene family, member B, also known as RHOB, is a protein which in humans is encoded by the RHOB gene.RHOB is a member of the Rho GTP-binding protein family.-Interactions:...
mRNA is a bona fide miR-223 target. miR-223 also regulates cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
activity by modulating expression of the FBXW7
FBXW7
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.-Interactions:FBXW7 has been shown to interact with PPARGC1A, Parkin , MYB and SKP1A.-Further reading:...
protein. In particular, overexpression of miR-223 reduces FBXW7 mRNA levels while increasing endogenous cyclin E protein and activity levels.
Role in hematopoiesis
The role of miR-223 in hematopoiesis has been extensively analyzed in the past few years. During granulopoiesisGranulopoiesis
Granulopoiesis is hematopoiesis of granulocytes.It occurs primarily within bone marrow and involves the following stages:* Pluripotential hemopoietic stem cell* Myeloblast* Promyelocyte* Eosino/neutro/basophilic myelocyte...
miR-223 acts as fine-tuner of granulocytic differentiation, maturation, and function. More specifically, human granulocytic differentiation is controlled by a regulatory circuitry involving miR-223 and two transcriptional factors, NFIA
NFIA
Nuclear factor 1 A-type is a protein that in humans is encoded by the NFIA gene....
and C/EBPα
Ccaat-enhancer-binding proteins
CCAAT-enhancer-binding proteins are a family of transcription factors, composed of six members called C/EBP α to C/EBP ζ. They promote the expression of certain genes through interaction with their promoter. Once bound to DNA, C/EBPs can recruit so-called coactivators CCAAT-enhancer-binding...
. These two factors compete for binding: NFI-A maintains miR-223 at low levels whereas C/EBPα upregulates miR-223 expression. The competition by C/EBPα and the granulocytic differentiation are favored by a negative-feedback loop in which miR-223 represses NFI-A translation.
Analysis of expression profiles indicate that miR-223 expression decreases as cells mature during monocytic, erythroid, and mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
differentiation. miR-223 down-regulation during erythropoiesis is required for erythrocyte proliferation and differentiation at progenitor and precursor level. This down-modulation promotes erythropoiesis favoring translation of the key functional protein LMO2
LMO2
LIM domain only 2 , also known as LMO2, is a protein which in humans is encoded by the LMO2 gene.- Function :LMO2 encodes a cysteine-rich, two LIM domain protein that is required for yolk sac erythropoiesis. The LMO2 protein has a central and crucial role in hematopoietic development and is highly...
resulting in reversible regulation of erythroid and megakaryocytic differentiation.
MicroRNA-223 also plays an essential role during osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
differentiation. More specifically, miR-223 expression suppresses the differentiation of osteoclast precursors into osteoclast thus making it a potential viable therapeutic target for a range of bone metabolic disorders with excess osteoclast activity.
Cancer
MicroRNA-223 is commonly repressed in hepatocellular carcinomaHepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
, chronic lymphocytic leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
, acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
, acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
, gastric MALT lymphoma
MALT lymphoma
MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue , frequently of the stomach, but virtually any mucosal site can be afflicted...
, and recurrent ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
.
Integrative analysis in hepatocellular carcinoma implicates Stathmin 1 (STMN1) as a downstream target of miR-223. Furthermore, miR-223 could suppress the luciferase activity in reporter construct containing the STMN1 3' untranslated region. The reduced expressions of miR-223 may predispose to the development of hepatocellular carcinoma via the widespread induction of chromosomal instability by STMN1.
MicroRNA-223 blocks the translation of E2F1
E2F1
Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene.-Interactions:E2F1 has been shown to interact with NCOA6, Retinoblastoma-like protein 1, Retinoblastoma protein, GTF2H1, SKP2, PURA, NPDC1, Sp2 transcription factor, Sp1 transcription factor, CUL1, ARID3A, TOPBP1,...
leading to inhibition of cell-cycle progression followed by myeloid differentiation. In acute myeloid leukemia (AML), miR-223 is down-regulated thus leading to E2F1 overexpression. The overexpressed E2F1 could bind to the miR-223 promoter and in turn lead to a further decrease in miR-223 expression through a negative feedback loop followed by myeloid cell-cycle progression at the expense of differentiation. Overexpression of E2F1 has been shown to be an oncogenic event that predisposes cells to transformation. While there is some indication of the miR-223 role in AML there is still little known about this microRNA function in chronic lymphocytic and acute lymphoblastic leukemia. Nevertheless, MicroRNA-223 expression levels decreased significantly with the progression of these two diseases thus associating miR-223 down-regulation with higher tumor burden, disease aggressiveness, and poor prognostic factors.
Gastric MALT lymphoma and recurrent ovarian cancer are associated with higher levels of MicroRNA-223 expression making them a potential biomarker.
Rheumatoid arthritis
MicroRNA-223 is overexpressed in the T-lymphocytes cells of rheumatoid arthritisRheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
patients suggesting that its expression in this cell type could contribute to the etiology of the disease.
Sepsis
There is some evidence that MicroRNA-223 and MicroRNA-146a are significantly reduced in septic patients compared with systemic inflammatory response syndromeSystemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
(SIRS) patients and/or healthy controls. This suggests that miR-223 can be used as a biomarker for distinguishing sepsis from SIRS.
Diabetes
Quantitative miRNA expression analyses revealed that miR-223 was consistently upregulated in the insulin-resistant hearts of patients with type 2 diabetesDiabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
. This effect was associated with miR-223 role in Glut4
GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
regulation and glucose metabolism.
Hepatic ischemia
A recent study concluded that hepatic ischemia/reperfusion injury might be another form of liver disease that is associated with the alteration in miR-223 expression. Correlation analysis revealed that hepatic miR-223 expression levels are significantly positively correlated with the serum markers of hepatic ischemia. Further, prediction assay of miRNA targets mRNA, acyl-CoA synthetase long-chain family member 3ACSL3
Long-chain-fatty-acid—CoA ligase 3 is an enzyme that in humans is encoded by the ACSL3 gene.-Further reading:...
, ephrin A1
Ephrin A1
Ephrin-A1 is a protein that in humans is encoded by the EFNA1 gene.-Further reading:...
, and ras homolog gene family member B
RHOB
Ras homolog gene family, member B, also known as RHOB, is a protein which in humans is encoded by the RHOB gene.RHOB is a member of the Rho GTP-binding protein family.-Interactions:...
were predicted to be downstream targets of miR-223.
See also
- MicroRNA
- Hepatocellular carcinomaHepatocellular carcinomaHepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
- Chronic lymphocytic leukemiaChronic lymphocytic leukemiaB-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
- Acute lymphoblastic leukemiaAcute lymphoblastic leukemiaAcute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
- Acute myeloid leukemiaAcute myeloid leukemiaAcute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
- gastric MALT lymphomaMALT lymphomaMALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue , frequently of the stomach, but virtually any mucosal site can be afflicted...
- Ovarian cancerOvarian cancerOvarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
- Rheumatoid arthritisRheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
- SepsisSepsisSepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
- Diabetes
- Hematopoiesis