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MIR222 (microRNA 222)

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

(Note : for Links provided by Atlas : click)


Alias (NCBI)MIRN222 (microRNA 222)
HGNC (Hugo) MIR222
HGNC Alias symbhsa-mir-222
HGNC Previous nameMIRN222
LocusID (NCBI) 407007
Atlas_Id 44278
Location Xp11.3  [Link to chromosome band Xp11]
Location_base_pair Starts at 45747015 and ends at 45747124 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping MIR222.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
  • Fusion genes
    (updated 2017)
    Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


      A: Stem-loop structure of miR-222. 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 222 (Precursor microRNA)
  • Accession: MI0000299
  • Length:110 bp
  • Sequence:

  • Mature miR-222
  • Accession: MIMAT0000279
  • Length: 21 nucleotides
  • Sequence: 69 - agcuacaucuggcuacugggu - 89
  • Pseudogene No pseudogenes were reported for mir-221 and 222.


    Note MicroRNAs are not translated into amino acids.

    Implicated in

    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. Such a fluctuation in the miRNA expression, however, 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 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 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 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 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.


    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.
    Dahiya N, Sherman-Baust CA, Wang TL, Davidson B, Shih IeM, Zhang Y, Wood W 3rd, Becker KG, Morin PJ.
    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.
    Proc Natl Acad Sci U S A. 2005; 102(50): 18081-6.
    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.
    J Biol Chem 2007; 282(32): 23716-24.
    PMID 17569667
    MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer.
    Garofalo M, Quintavalle C, Di Leva G, Zanca C, Romano G, Taccioli C, Liu CG, Croce CM, Condorelli G.
    Oncogene 2008; 27(27): 3845-55.
    PMID 18246122
    MicroRNA profiling in kidney and bladder cancers.
    Gottardo F, Liu CG, Ferracin M, Calin GA, Fassan M, Bassi P, Sevignani C, Byrne D, Negrini M, Pagano F, Gomella LG, Croce CM, Baffa R.
    Urol Oncol 2007; 25(5): 387-92.
    PMID 17826655
    The role of microRNA genes in papillary thyroid carcinoma.
    He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, Calin GA., Liu C-G, Franssila K, Suster S, Kloos RT, Croce CM, de la Chapelle.A
    PNAS 2005; 52, 19075-19080.
    PMID 16365291
    Targeting microRNA expression to regulate angiogenesis.
    Kuehbacher A, Urbich C, Dimmeler S.
    Trends Pharmacol Sci 2008; 29(1): 12-5.
    PMID 18068232
    Expression profiling identifies microRNA signature in pancreatic cancer.
    Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, Morgan DL, Postier RG, Brackett DJ, Schmittgen TD.
    Int J Cancer 2007; 120(5): 1046-54.
    PMID 17149698
    MicroRNA expression profiles classify human cancers.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR.
    Nature 2005; 435(7043): 834-8.
    PMID 15944708
    Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis.
    Masaki S, Ohtsuka R, Abe Y, Muta K, Umemura T.
    Biochem Biophys Res Commun 2007; 364(3): 509-14.
    PMID 17964546
    Peptide-15 Changes miRNA Expression in Osteoblast-Like Cells.
    Palmieri A, Pezzetti F, Brunelli G, Martinelli M, Lo Muzio L, Scarano A, Degidi M, Piattelli A, Carinci F.
    Implant Dent 2008; 17(1): 100-8.
    PMID 18332763
    MicroRNAs modulate the angiogenic properties of HUVECs.
    Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G.
    Blood 2006; 108(9): 3068-71.
    PMID 16849646
    MYCN regulates oncogenic MicroRNAs in neuroblastoma.
    Schulte JH, Horn S, Otto T, Samans B, Heukamp LC, Eilers UC, Krause M, Astrahantseff K, Klein-Hitpass L, Buettner R, Schramm A, Christiansen H, Eilers M, Eggert A, Berwanger B.
    Int J Cancer 2008; 122(3): 699-704.
    PMID 17943719
    Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells.
    Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC.
    Circ Res 2007; 100(8): 1164-73.
    PMID 17379831


    This paper should be referenced as such :
    Tabasi, SA ; Erson, AE
    MIR222 (microRNA 222)
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(8):566-569.
    Free journal version : [ pdf ]   [ DOI ]

    External links

    HGNC (Hugo)MIR222   31602
    Atlas Explorer : (Salamanque)MIR222
    Entrez_Gene (NCBI)MIR222    microRNA 222
    AliasesMIRN222; miRNA222; mir-222
    GeneCards (Weizmann)MIR222
    Ensembl hg19 (Hinxton)ENSG00000207725 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000207725 [Gene_View]  ENSG00000207725 [Sequence]  chrX:45747015-45747124 [Contig_View]  MIR222 [Vega]
    ICGC DataPortalENSG00000207725
    TCGA cBioPortalMIR222
    AceView (NCBI)MIR222
    Genatlas (Paris)MIR222
    SOURCE (Princeton)MIR222
    Genetics Home Reference (NIH)MIR222
    Genomic and cartography
    GoldenPath hg38 (UCSC)MIR222  -     chrX:45747015-45747124 -  Xp11.3   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)MIR222  -     Xp11.3   [Description]    (hg19-Feb_2009)
    GoldenPathMIR222 - Xp11.3 [CytoView hg19]  MIR222 - Xp11.3 [CytoView hg38]
    Genome Data Viewer NCBIMIR222 [Mapview hg19]  
    Gene and transcription
    Genbank (Entrez)AJ550426 LM608367
    RefSeq transcript (Entrez)
    Consensus coding sequences : CCDS (NCBI)MIR222
    Gene ExpressionMIR222 [ NCBI-GEO ]   MIR222 [ EBI - ARRAY_EXPRESS ]   MIR222 [ SEEK ]   MIR222 [ MEM ]
    Gene Expression Viewer (FireBrowse)MIR222 [ Firebrowse - Broad ]
    GenevisibleExpression of MIR222 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)407007
    GTEX Portal (Tissue expression)MIR222
    Human Protein AtlasENSG00000207725-MIR222 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    Domain families : Pfam (Sanger)
    Domain families : Pfam (NCBI)
    Conserved Domain (NCBI)MIR222
    Human Protein Atlas [tissue]ENSG00000207725-MIR222 [tissue]
    Protein Interaction databases
    Ontologies - Pathways
    PubMed262 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Thu Jan 20 14:12:03 CET 2022

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