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MIR221 (microRNA 221)

Written2008-09Shiva Akhavan Tabasi, Ayse Elif Erson
Department of Biology, Middle East Technical University, Ankara, Turkey

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMIRN221
Alias_symbol (synonym)hsa-mir-221
Other aliasMIRN221 (microRNA 221)
miR-221
HGNC (Hugo) MIR221
LocusID (NCBI) 407006
Atlas_Id 44277
Location Xp11.3  [Link to chromosome band Xp11]
Location_base_pair Starts at 45746157 and ends at 45746266 bp from pter ( according to hg19-Feb_2009)  [Mapping MIR221.png]
Local_order Based on Mapviewer (Master Map: Genes on sequence), genes flanking miR-221 and miR-222 oriented from centromere to telomere on Xp11.3 are:
  • KRT8P14 (Xp11.3) : keratin 8 pseudogene 14
  • LOC392452 (Xp11.3) : hypothetical LOC392452
  • MIRN221 (Xp11.3) : microRNA 221
  • MIRN222 (Xp11.3) : microRNA 222
  • LOC100128442 (Xp11.3) : hypothetical LOC100128442
  • LOC100130359 (Xp11.3) : hypothetical LOC100130359
  • DNA/RNA

     
      Figure1: A: Stem-loop structure of miR-221. B: Genomic localization of miR-221 (MIRN221) and miR-221(MIRN222) on chromosomal band Xp11.3.
    Description miR-221 and 222 are located in an intergenic region. miR-221 and miR-222 are clustered genes, containing identical seed sequences and both map to the X chromosome separated by 727 bases. The positions of these cluster microRNAs are:
  • hsa-mir-222 X: 45491365-45491474
  • has-mir-221 X: 45490529-45490638
  • Transcription In general, the microRNA genes are transcribed by RNA polymerase II, whereas RNA polymerase III is also responsible for transcription of some other microRNAs. It is not known which RNA polymerase transcribes miR 221/miR-222. miR-221 and miR-222 were shown to be expressed as a single pri-microRNA transcript in c-kit positive HUVEC cells.
  • Pre-microRNA 221(Precursor microRNA)
  • Accession: MI0000298
  • Length: 110 bp
  • Sequence:
    5'-UGAACAUCCAGGUCUGGGGCAUGAACCUGGCAUACAAUGUAGAUUUCUGUGUUC
    GUUAGGCAACAGCUACAUUGUCUGCUGGGUUUCAGGCUACCUGGAAACAUGUUCUC -3'
  • Mature miR-221
  • Accession: MIMAT0000278
  • Length: 23 nucleotides
  • Sequence: 65 - agcuacauugucugcuggguuuc - 87
  • Pseudogene No pseudogenes were reported for mir-221 and 222.

    Protein

    Note MicroRNAs are not translated into amino acids.

    Implicated in

    Note
      
    Entity Differentiation and erythropoiesis
    Note Induction of 12-O-tetradecanoylphorbol-13-acetate (TPA), a differentiation stimulator of HL-60 cells, caused growth arrest and the adherent phenotype in 60% of HL-60 cells. MicroRNA expression was analyzed in these TPA treated differentiating HL-60 cells. According to the results of microarray analysis, miR-221 and miR-222 were up-regulated about 3-folds in TPA induced HL-60 cells. On the other hand, the expression of c-kit receptor was down- regulated in these cells, which suggested that c-kit, as was previously reported, the target of miR-221/222.
    miR-221 and miR-222 were shown to be down-regulated in erythropoietic culture of cord blood CD34-positive progenitor cells and it was suggested that this reduction could cause erythropoiesis, as the expression of targeted key mRNAs were not blocked. However in another study, the expression of miR-221 (but not miR-222) was shown to be increased during erythropoietic cultures of human CD34 cord blood cells. Further studies also indicated up-regulation of miR-221. Differentially expressed miRNAs during erythropoiesis were detected in cord blood-derived CD34 cells and expression of miR-221 temporarily increased from day 0 to day 2, while its expression returned to the basal level (same as day 0) from day 2 to day 12 of erythropoiesis. However such a fluctuation in the miRNA expression was not found for miR-222 in these cells. Together, these results suggest a need for further investigation to clarify this difference.
    Also in kit positive TF-1 erythroleukemic cell line which expresses high amounts of kit protein and low levels of miR-221/miR-222, transfection of these microRNAs blocked proliferation of these cells.
      
      
    Entity Angiogenesis, proliferation and cell migration
    Note miR-222 and miR-221 were found to be highly expressed in human cord blood derived CD34 - Hematopoietic Progenitor Cells (HPCs) and Human Umbilical Vein Endothelial cells (HUVECs). HUVECs were used as an in vitro model for angiogenesis as they can form capillary like tubes when exposed to appropriate stimulation. miR-221/miR-222 were shown to be transcribed in a common pri-microRNA in c-kit-positive HUVECs, suggesting a coordinated transcriptional regulation. Another group examined the effect of miR-221/miR-222 expression on the c-kit transcript and protein and they found that the level of c-kit protein was reduced in HUVECs transfected with miR-221/ miR-222, without a change of mRNA levels, which indicated the posttranslational down-regulation effect of these microRNAs on c-kit protein. In addition miR-221/miR-222 transfected cells were not able to do wound healing and tube formation. In another study, down-regulation of eNOS (an angiogenesis regulator) protein by miR-221/miR-222 was claimed and because no target sites for these microRNAs in 3'-UTR of eNOS were present, it was suggested that the regulation could be indirect via gene expression, translational efficiency or post-translational pathways. Interestingly, over-expression of miR-221/miR-222 in endothelial cells reduced angiogenesis and cell proliferation whereas conversely in cancer cells, up-regulation of miR-221/miR-222 increased cell proliferation by targeting cell cycle inhibitor p27, possibly indicating that the modulation of proliferation depends on the cell type.
      
      
    Entity Glioblastoma
    Note Glioblastoma tissues and cell lines were investigated for differentially expressed microRNAs compared to normal brain tissue. Microarray and Northern blot results showed a strong up- regulation of miR-221 in glioblastomas.
      
      
    Entity Prostate cancer
    Note In a study, PC3 cells (aggressive prostate carcinoma) and LNCaP and 22Rv1 cell line (slowly growing carcinomas) were tested and a reverse correlation between the expression of miR-221/miR-222 and p27 tumor suppressor was observed. In addition, over-expression of miR-221/miR-222 altered the growth rate of these cells, by triggering a shift from G1 to S phase of the cell cycle.
      
      
    Entity Ovarian cancer
    Note A microRNA microarray study was performed to detect the microRNA expression level in ovarian cancer, using 34 ovarian cancer tissues and 10 ovarian cancer cell lines. The results showed that miR-221 was the most highly expressed microRNA in both ovarian cancer tissues and cell lines compared to non-transformed human ovarian surface epithelium cell line.
      
      
    Entity Bladder cancer
    Note Based on a microarray study, it was shown that human miR-221 was among the remarkably up-regulated microRNAs in bladder cancers when compared to normal bladder mucosa. In this study, a microchip containing 368 probes in triplicate designed for 245 microRNA genes were used for 27 bladder specimens (25 urothelial carcinomas and 2 normal mucosa samples).
      
      
    Entity Papillary thyroid carcinoma
    Note When comparing the expression level of 23 microRNAs in 15 Papillary Thyroid Cancer (PTC) tumors with normal thyroid tissue, a group of researchers found that miR-221/ miR-222 were among the five over-expressed microRNAs in PTC tumors by performing microarray analysis (the results were also confirmed with RT-PCR and Northern blot). Interestingly, quantitative real-time PCR results revealed that miR-221 was over-expressed in normal thyroid tissues of PTC patients when compared to normal thyroid tissues of individuals without clinical thyroid disease, indicating the possible importance of this microRNA in early stages of PTC carcinogenesis.
      
      
    Entity Hepatocellular carcinoma
    Note As it has been shown in many cancers, miR-221 was also found to be up-regulated in human hepatocellular carcinoma (HCC). Over-expression of miR-221 was shown to cause down- regulation of CDKN1B/p27 and CDKN1C/p57 in hepatocellular carcinoma, indicating a reverse relation between their expressions in HCC. miR-221 was shown to target 3' UTRs of CDKN1B/p27 and CDKN1C/p57. Up-regulation of miR-221 caused cell proliferation in HCC cells by increasing the number of cells which were in S1 phase of the cell cycle.
      
      
    Entity Osteogenesis
    Note P-15 is an analog of cell-binding domain of collagen and is involved in binding, migration and differentiation of cells and promoting bone formation from osteoblasts. To understand the mechanism of action of P-15, the expression of microRNAs in osteoblast-like cell line (MG-63) cultured with P-15 was investigated and miR-221 was among the up-regulated ones according to a microRNA microarray study.
      
      
    Entity Lung cancer
    Note A microRNA expression investigation was performed in NSCLC (Non-Small Cell Lung Cancer) cells either resistant or sensitive to TRAIL (TNF-related apoptosis-inducing ligand) to reveal roles of microRNAs in TRAIL resistance. The microarray and real-time PCR analysis showed that miR-221 and miR-222 were remarkably up-regulated in TRAIL-resistant and down-regulated in TRAIL-sensitive NSCLC cells. Also miR-222 over-expression in CALU-1 cells (TRAIL-resistant) was confirmed by Northern blotting. In addition, transfecting CALU-1 cells (TRAIL-resistant lung cells) with anti- miR-221/miR-222, caused TRAIL sensitivity. Consistently over-expression of these microRNAs produced TRAIL-resistant NSCLC cells. Moreover, p27 tumor suppressor and proto-oncogene kit receptor, which are the known targets of miR-221/miR-222, were shown to be up-regulated in TRAIL-sensitive and down-regulated in TRAIL-resistant NSCLC. These microRNAs were also suggested to modulate the expression of Mcl-1 (Myeloid cell leukemia sequence 1) and FADD (Fas-Associated protein with Death Domain) indirectly. Giving these, miR-221 and miR-222 were shown to be responsible for sensitivity to TRAIL in NSCLC cells and could be considered as important targets for diagnostic and therapeutic purposes in NSCLC.
      
      
    Entity Neuroblastoma
    Note MYCN amplification is commonly found in neuroblastomas. MYCN acts as transcription factor and regulates the expression of a number of genes. For finding the microRNA genes that are possibly regulated with MYCN, microarray and q-RT-PCR studies were performed in primary neuroblastoma with MYCN amplification. miR-221 was one of the 7 up-regulated microRNAs in these cells.
      
      
    Entity Pancreatic cancer
    Note For the purpose of finding a microRNA signature in pancreatic cancers, the expression of over 200 microRNA precursors was investigated by real-time PCR in benign tissue, normal pancreas, chronic pancreatitis and pancreatic cancer cell lines. The results showed that a number of microRNAs were over-expressed in the tumors, when compared to normal pancreas. miR-221 was among the microRNAs that were over-expressed in adenocarcinomas and endocrine pancreas cancers. Based on PCR results, over-expression of mature miR-222 was also suggested (similar to miR-221) in pancreas cancer.
      

    Bibliography

    MicroRNA expression profiling during human cord blood-derived CD34 cell erythropoiesis.
    Choong ML, Yang HH, McNiece I.
    Exp Hematol 2007; 35(4): 551-64.
    PMID 17379065
     
    Extensive modulation of a set of microRNAs in primary glioblastoma.
    Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, Negrini M, Maira G, Croce CM, Farace MG.
    Biochem Biophys Res Commun 2005; 334(4): 1351-8.
    PMID 16039986
     
    MicroRNA Expression and Identification of Putative miRNA Targets in Ovarian Cancer.
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    PLoS ONE 2008; 3(6): e2436.
    PMID 18560586
     
    MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor downmodulation.
    Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, Liuzzi F, Lulli V, Morsilli O, Santoro S, Valtieri M, Calin GA, Liu CG, Sorrentino A, Croce CM, Peschle C.
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    PMID 16330772
     
    MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma.
    Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Giovannini C, Croce CM, Bolondi L, Negrini M.
    Oncogene 2008; 27(43): 5651-61.
    PMID 18521080
     
    miR-221 and miR-222 Expression Affects the Proliferation Potential of Human Prostate Carcinoma Cell Lines by Targeting p27Kip1.
    Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafre SA, Farace MG.
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    PMID 17569667
     
    MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer.
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    Oncogene 2008; 27(27): 3845-55.
    PMID 18246122
     
    MicroRNA profiling in kidney and bladder cancers.
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    Urol Oncol 2007; 25(5): 387-92.
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    The role of microRNA genes in papillary thyroid carcinoma.
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    Targeting microRNA expression to regulate angiogenesis.
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    Trends Pharmacol Sci 2008; 29(1): 12-5.
    PMID 18068232
     
    Expression profiling identifies microRNA signature in pancreatic cancer.
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    Int J Cancer 2007; 120(5): 1046-54.
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    MicroRNA expression profiles classify human cancers.
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    PMID 15944708
     
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    PMID 17964546
     
    Peptide-15 Changes miRNA Expression in Osteoblast-Like Cells.
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    MicroRNAs modulate the angiogenic properties of HUVECs.
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    Citation

    This paper should be referenced as such :
    Tabasi, SA ; Erson, AE
    MIR221 (microRNA 221)
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(8):562-565.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/MIRN221ID44277chXp11.html


    External links

    Nomenclature
    HGNC (Hugo)MIR221   31601
    Cards
    AtlasMIRN221ID44277chXp11
    Entrez_Gene (NCBI)MIR221  407006  microRNA 221
    AliasesMIRN221; miRNA221; mir-221
    GeneCards (Weizmann)MIR221
    Ensembl hg19 (Hinxton)ENSG00000207870 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000207870 [Gene_View]  chrX:45746157-45746266 [Contig_View]  MIR221 [Vega]
    ICGC DataPortalENSG00000207870
    TCGA cBioPortalMIR221
    AceView (NCBI)MIR221
    Genatlas (Paris)MIR221
    WikiGenes407006
    SOURCE (Princeton)MIR221
    Genetics Home Reference (NIH)MIR221
    miRBaseMIR221
    dbDEMCMIR221
    Genomic and cartography
    GoldenPath hg38 (UCSC)MIR221  -     chrX:45746157-45746266 -  Xp11.3   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)MIR221  -     Xp11.3   [Description]    (hg19-Feb_2009)
    EnsemblMIR221 - Xp11.3 [CytoView hg19]  MIR221 - Xp11.3 [CytoView hg38]
    Mapping of homologs : NCBIMIR221 [Mapview hg19]  MIR221 [Mapview hg38]
    OMIM300568   
    Gene and transcription
    Genbank (Entrez)AJ550425 LM608366
    RefSeq transcript (Entrez)
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)MIR221
    Alternative Splicing GalleryENSG00000207870
    Gene ExpressionMIR221 [ NCBI-GEO ]   MIR221 [ EBI - ARRAY_EXPRESS ]   MIR221 [ SEEK ]   MIR221 [ MEM ]
    Gene Expression Viewer (FireBrowse)MIR221 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    BioGPS (Tissue expression)407006
    GTEX Portal (Tissue expression)MIR221
    Protein : pattern, domain, 3D structure
    Domain families : Pfam (Sanger)
    Domain families : Pfam (NCBI)
    Conserved Domain (NCBI)MIR221
    DMDM Disease mutations407006
    Blocks (Seattle)MIR221
    Human Protein AtlasENSG00000207870
    Protein Interaction databases
    FunCoupENSG00000207870
    BioGRIDMIR221
    STRING (EMBL)MIR221
    ZODIACMIR221
    Ontologies - Pathways
    Huge Navigator MIR221 [HugePedia]
    snp3D : Map Gene to Disease407006
    BioCentury BCIQMIR221
    ClinGenMIR221
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD407006
    Chemical/Pharm GKB GenePA164722609
    Clinical trialMIR221
    Miscellaneous
    canSAR (ICR)MIR221 (select the gene name)
    Probes
    Litterature
    PubMed206 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineMIR221
    EVEXMIR221
    GoPubMedMIR221
    iHOPMIR221
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Fri Jun 30 11:12:06 CEST 2017

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