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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.
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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.[7] MicroRNA-223 is also associated with rheumatoid arthritis,[12] sepsis,[13] type 2 diabetes,[14] and hepatic ischemia.[15]
[edit] Characterization
MicroRNA-223 was initially identified bioinformatically and it was subsequently characterized as part of the haematopoietic system.[2] 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]
[edit] Role in hematopoiesis
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.[2][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.[4]
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]
[edit] Involvement in disease
[edit] Cancer
MicroRNA-223 is commonly repressed in hepatocellular carcinoma,[5] chronic lymphocytic leukemia,[7] acute lymphoblastic leukemia,[8] acute myeloid leukemia,[6][9] gastric MALT lymphoma,[10] 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.[5] The reduced expressions of miR-223 may predispose to the development of hepatocellular carcinoma via the widespread induction of chromosomal instability by STMN1.[5]
MicroRNA-223 blocks the translation of E2F1 leading to inhibition of cell-cycle progression followed by myeloid differentiation.[9] 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 [10][11] making them a potential biomarker.
[edit] Rheumatoid arthritis
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.[12]
[edit] Sepsis
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.[13] This suggests that miR-223 can be used as a biomarker for distinguishing sepsis from SIRS.
[edit] Diabetes
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.[14]
[edit] 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.[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.
[edit] See also
[edit] References
- ^ Sun W, Shen W, Yang S, Hu F, Li H, Zhu TH (2010). "miR-223 and miR-142 attenuate hematopoietic cell proliferation, and miR-223 positively regulates miR-142 through LMO2 isoforms and CEBP-β.". Cell Res 20 (10): 1158–69. doi:10.1038/cr.2010.134. PMID 20856265.
- ^ a b c d Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, Brummelkamp TR, Fleming MD, Camargo FD (2008). "Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.". Nature 451 (7182): 1125–9. doi:10.1038/nature06607. PMID 18278031.
- ^ Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, Diverio D, Ammatuna E, Cimino G, Lo-Coco F, Grignani F, Nervi C (2007). "Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein.". Cancer Cell 12 (5): 457–66. doi:10.1016/j.ccr.2007.09.020. PMID 17996649.
- ^ a b Yuan JY, Wang F, Yu J, Yang GH, Liu XL, Zhang JW. "MicroRNA-223 reversibly regulates erythroid and megakaryocytic differentiation of K562 cells.". J Cell Mol Med 13 (11-12): 4551–9. doi:10.1111/j.1582-4934.2008.00585.x. PMID 19017354.
- ^ a b c d Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N (2008). "MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1.". Gastroenterology 135 (1): 257–69. doi:10.1053/j.gastro.2008.04.003. PMID 18555017.
- ^ a b c Eyholzer M, Schmid S, Schardt JA, Haefliger S, Mueller BU, Pabst T (2010). "Complexity of miR-223 regulation by CEBPA in human AML.". Leuk Res 34 (5): 672–6. doi:10.1016/j.leukres.2009.11.019. PMID 20018373.
- ^ a b c d Stamatopoulos B, Meuleman N, Haibe-Kains B, Saussoy P, Van Den Neste E, Michaux L, Heimann P, Martiat P, Bron D, Lagneaux L (2009). "microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification.". Blood 113 (21): 5237–45. doi:10.1182/blood-2008-11-189407. PMID 19144983.
- ^ a b c Chiaretti S, Messina M, Tavolaro S, Zardo G, Elia L, Vitale A, Fatica A, Gorello P, Piciocchi A, Scappucci G, Bozzoni I, Fozza C, Candoni A, Guarini A, Foà R (2010). "Gene expression profiling identifies a subset of adult T-cell acute lymphoblastic leukemia with myeloid-like gene features and over-expression of miR-223.". Haematologica 95 (7): 1114–21. doi:10.3324/haematol.2009.015099. PMID 20418243.
- ^ a b c Pulikkan JA, Dengler V, Peramangalam PS, Peer Zada AA, Müller-Tidow C, Bohlander SK, Tenen DG, Behre G (2010). "Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia.". Blood 115 (9): 1768–78. doi:10.1182/blood-2009-08-240101. PMID 20029046.
- ^ a b c Liu TY, Chen SU, Kuo SH, Cheng AL, Lin CW (2010). "E2A-positive gastric MALT lymphoma has weaker plasmacytoid infiltrates and stronger expression of the memory B-cell-associated miR-223: possible correlation with stage and treatment response.". Mod Pathol 23 (11): 1507–17. doi:10.1038/modpathol.2010.139. PMID 20802470.
- ^ a b c Laios A, O'Toole S, Flavin R, Martin C, Kelly L, Ring M, Finn SP, Barrett C, Loda M, Gleeson N, D'Arcy T, McGuinness E, Sheils O, Sheppard B, O' Leary J (2008). "Potential role of miR-9 and miR-223 in recurrent ovarian cancer.". Mol Cancer 7: 35. doi:10.1186/1476-4598-7-35. PMC 2383925. PMID 18442408. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2383925/.
- ^ a b Fulci V, Scappucci G, Sebastiani GD, Giannitti C, Franceschini D, Meloni F, Colombo T, Citarella F, Barnaba V, Minisola G, Galeazzi M, Macino G (2010). "miR-223 is overexpressed in T-lymphocytes of patients affected by rheumatoid arthritis.". Hum Immunol 71 (2): 206–11. doi:10.1016/j.humimm.2009.11.008. PMID 19931339.
- ^ a b Wang JF, Yu ML, Yu G, Bian JJ, Deng XM, Wan XJ, Zhu KM (2010). "Serum miR-146a and miR-223 as potential new biomarkers for sepsis.". Biochem Biophys Res Commun 394 (1): 184–8. doi:10.1016/j.bbrc.2010.02.145. PMID 20188071.
- ^ a b Lu Han, Buchan Rachel, Cook Stuart (2010). "MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism". Cardiovasc Res 86 (3): 410–420. doi:10.1093/cvr/cvq010. PMID 20080987.
- ^ a b Yu CH, Xu CF, Li YM (2009). "Association of MicroRNA-223 expression with hepatic ischemia/reperfusion injury in mice.". Dig Dis Sci 54 (11): 2362–6. doi:10.1007/s10620-008-0629-8. PMID 19104939.
- ^ Fukao T, Fukuda Y, Kiga K, Sharif J, Hino K, Enomoto Y, Kawamura A, Nakamura K, Takeuchi T, Tanabe M (2007). "An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling.". Cell 129 (3): 617–31. doi:10.1016/j.cell.2007.02.048. PMID 17482553.
- ^ Sun G, Li H, Rossi JJ (2010). "Sequence context outside the target region influences the effectiveness of miR-223 target sites in the RhoB 3'UTR.". Nucleic Acids Res 38 (1): 239–52. doi:10.1093/nar/gkp870. PMID 19850724.
- ^ Xu Y, Sengupta T, Kukreja L, Minella AC (2010). "MicroRNA-223 regulates cyclin E activity by modulating expression of F-box and WD-40 domain protein 7.". J Biol Chem 285 (45): 34439–46. doi:10.1074/jbc.M110.152306. PMID 20826802.
- ^ a b c Felli N, Pedini F, Romania P, Biffoni M, Morsilli O, Castelli G, Santoro S, Chicarella S, Sorrentino A, Peschle C, Marziali G (2009). "MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis.". Haematologica 94 (4): 479–86. doi:10.3324/haematol.2008.002345. PMID 19278969.
- ^ Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I (2005). "A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis.". Cell 123 (5): 819–31. doi:10.1016/j.cell.2005.09.023. PMID 16325577.
- ^ Sugatani T, Hruska KA (2007). "MicroRNA-223 is a key factor in osteoclast differentiation.". J Cell Biochem 101 (4): 996–9. doi:10.1002/jcb.21335. PMID 17471500.
[edit] Further reading
- Song, L; Duan, P; Guo, P; Li, D; Li, S; Xu, Y; Zhou, Q (2012 Dec 15). "Downregulation of miR-223 and miR-153 mediates mechanical stretch-stimulated proliferation of venous smooth muscle cells via activation of the insulin-like growth factor-1 receptor.". Archives of biochemistry and biophysics 528 (2): 204-11. doi:10.1016/j.abb.2012.08.015. PMID 23046980.
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