| mir-223 | |
| Width: | 220px |
| Symbol: | mir-223 |
| Rfam: | RF00664 |
| Mirbase Family: | MIPF0000067 |
| Rna Type: | microRNA |
| Tax Domain: | Eukaryota |
| Entrezgene: | 407008 |
| Hgncid: | 31603 |
| Omim: | 300694 |
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.[1] [2] It plays an essential role in promoting granulocytic differentiation[2] [3] while also being associated with the suppression of erythrocytic differentiation.[4] miR-223 is commonly repressed in hepatocellular carcinoma[5] and leukemia.[6] [7] [8] [9] Higher expression levels of miRNA-223 are associated with extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the stomach[10] and recurrent ovarian cancer.[11] 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,[12] sepsis,[13] type 2 diabetes,[14] and hepatic ischemia.[15]
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/EBPα proteins which are myeloid transcription factors.[16]
MicroRNA-223 selectively targets distinct populations of transcripts harboring AU-rich elements. More specifically, it was validated that the RhoB mRNA is a bona fide miR-223 target.[17] 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.[18]
The role of miR-223 in hematopoiesis has been extensively analyzed in the past few years. During granulopoiesis miR-223 acts as fine-tuner of granulocytic differentiation, maturation, and function.[19] 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.[20]
Analysis of expression profiles indicate that miR-223 expression decreases as cells mature during monocytic, erythroid, and mast cell differentiation.[19] miR-223 down-regulation during erythropoiesis is required for erythrocyte proliferation and differentiation at progenitor and precursor level.[19] 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.[21]
MicroRNA-223 is commonly repressed in hepatocellular carcinoma, chronic lymphocytic leukemia,[7] acute lymphoblastic leukemia,[8] acute myeloid leukemia,[6] gastric MALT lymphoma, and recurrent ovarian cancer.[11]
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.[6] 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.[7] [8]
Gastric MALT lymphoma and recurrent ovarian cancer are associated with higher levels of MicroRNA-223 expression[11] making them a potential biomarker.
MicroRNA-223 is overexpressed in the T-lymphocytes cells of rheumatoid arthritis patients suggesting that its expression in this cell type could contribute to the etiology of the disease.
There is some evidence that MicroRNA-223 and MicroRNA-146a are significantly reduced in septic patients compared with systemic inflammatory response syndrome (SIRS) patients and/or healthy controls. This suggests that miR-223 can be used as a biomarker for distinguishing sepsis from SIRS.
Quantitative miRNA expression analyses revealed that miR-223 was consistently upregulated in the insulin-resistant hearts of patients with type 2 diabetes. This effect was associated with miR-223 role in Glut4 regulation and glucose metabolism.
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.[15] 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 3, ephrin A1, and ras homolog gene family member B were predicted to be downstream targets of miR-223.