MIR221 (microRNA 221)

2008-09-01   Shiva Akhavan Tabasi , Ayse Elif Erson 

Department of Biology, Middle East Technical University, Ankara, Turkey

Identity

HGNC
LOCATION
Xp11.3
LOCUSID
ALIAS
MIRN221 (microRNA 221),hsa-mir-221,miR-221

DNA/RNA

Atlas Image
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.

    Proteins

    Note

    MicroRNAs are not translated into amino acids.

    Implicated in

    Entity name
    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 name
    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 name
    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 name
    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 name
    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 name
    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 name
    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 name
    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 name
    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 name
    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 name
    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 name
    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

    Pubmed IDLast YearTitleAuthors
    173790652007MicroRNA expression profiling during human cord blood-derived CD34 cell erythropoiesis.Choong ML et al
    160399862005Extensive modulation of a set of microRNAs in primary glioblastoma.Ciafrè SA et al
    185605862008MicroRNA expression and identification of putative miRNA targets in ovarian cancer.Dahiya N et al
    163307722005MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.Felli N et al
    185210802008MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma.Fornari F et al
    175696672007miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1.Galardi S et al
    182461222008MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer.Garofalo M et al
    178266552007Micro-RNA profiling in kidney and bladder cancers.Gottardo F et al
    163652912005The role of microRNA genes in papillary thyroid carcinoma.He H et al
    180682322008Targeting microRNA expression to regulate angiogenesis.Kuehbacher A et al
    171496982007Expression profiling identifies microRNA signature in pancreatic cancer.Lee EJ et al
    159447082005MicroRNA expression profiles classify human cancers.Lu J et al
    179645462007Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis.Masaki S et al
    183327632008Peptide-15 changes miRNA expression in osteoblast-like cells.Palmieri A et al
    168496462006MicroRNAs modulate the angiogenic properties of HUVECs.Poliseno L et al
    179437192008MYCN regulates oncogenic MicroRNAs in neuroblastoma.Schulte JH et al
    173798312007Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells.Suárez Y et al

    Other Information

    Locus ID:

    NCBI: 407006
    MIM: 300568
    HGNC: 31601
    Ensembl: ENSG00000207870
    miRBase:

    Variants:

    dbSNP: 407006
    ClinVar: 407006
    TCGA: ENSG00000207870
    COSMIC: MIR221

    RNA/Proteins

    Expression (GTEx)

    0
    5
    10
    15

    Pathways

    PathwaySourceExternal ID
    MicroRNAs in cancerKEGGhsa05206
    MicroRNAs in cancerKEGGko05206

    References

    Pubmed IDYearTitleCitations
    163652912005The role of microRNA genes in papillary thyroid carcinoma.382
    199626682009miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation.305
    187083512008MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1.300
    185210802008MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma.229
    208183872010A Pumilio-induced RNA structure switch in p27-3' UTR controls miR-221 and miR-222 accessibility.168
    179141082007MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle.141
    190880792009Induction of microRNA-221 by platelet-derived growth factor signaling is critical for modulation of vascular smooth muscle phenotype.133
    208801782010Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression.120
    196718672009MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality.117
    208130462010MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma.108

    Citation

    Shiva Akhavan Tabasi ; Ayse Elif Erson

    MIR221 (microRNA 221)

    Atlas Genet Cytogenet Oncol Haematol. 2008-09-01

    Online version: http://atlasgeneticsoncology.org/gene/44277/mir221