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ANXA1 (annexin A1)

Identity

Other namesANX1
LPC1
HGNC (Hugo) ANXA1
LocusID (NCBI) 301
Location 9q21.13
Location_base_pair Starts at 75766781 and ends at 75785307 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order According to NCBI Map Viewer, genes flanking ANXA1 in centromere to telomere direction on 9q21 are: LOC100289351, RPS20P24, TMC1, RPS27AP15, ALDH1A1, LOC100133307, LOC100132782, ANXA1, LOC138971, LOC100130911, RORB, TRPM6, RNY4P1.

DNA/RNA

 
  ANXA1 gene. The ANXA1 gene contains 13 exons, of which the first and last are uncoding 5' and 3' sequences (red regions), with the translation initiator codon (AUG) found near the beginning of the second exon (orange regions).
Description The exon-intron organization of ANXA1 genes in vertebrates have been described and are highly conserved, each gene consisting of 13 exons of which the first and last are uncoding 5' and 3' sequences, with the translation initiator codon (AUG) found near the beginning of the second exon (Kovacic et al., 1991).
Transcription Transcription produces 9 different mRNAs to this gene. The ANXA1 gene is expressed in the tissues: bone, bone marrow, brain, cartilage, cerebellum, cerebrum, cervix, colon, ear, embryonic tissue, endocrine, esophagus, eye, fetus, gastrointestinal tract, heart, kidney, liver, lung, lymph node, lymphoreticular, mammary gland, muscle, nervous, ovary, pancreas, pancreatic islet, parathyroid, peripheral nervous system, pituitary gland, placenta, pooled tissue, prostate, salivary gland, skin, soft tissue, spleen, stem cell, stomach, synovium, t-cell, testis, thymus, thyroid, uncharacterized tissue, uterus, vascular.
Pseudogene No known pseudogenes.

Protein

Note Belongs to the annexin family. Contains 4 annexin repeats.
 
  Schematic representation of annexin protein. N-terminal region with amino acids and four repetitions with 70-75 amino acids in C-terminal region.
Description The ANXA1 gene encodes a 38.71 kDa protein. Similarly to other annexins, annexin A1 is characterized by a C-terminal homologous domain with 4 to 8 repeats of 70-75 aminoacids, responsible for calcium and phospholipid binding properties. The variable N-terminal region is unique in length and sequence and includes potential sites of phosphorylation, glycosylation and peptidase action (Gerke and Moss, 2002).
Expression The human ANXA1 gene promoter contains consensus sequences for: glucocorticoids, AP-1 and NFIL-6. However the regulation from glucocorticoid (GC) appear to be dependent upon an activation involving NFIL-6 or AP1 (Solito et al., 1998a; Solito et al., 1998b). The GC mediated regulations confirm the original studies which proposed ANXA1 as mediator of the glucocorticoid action (Flower, 1988). In mouse, in contrast, GC regulation is mediated through two consensus sequences present in the upstream region of TATA box (Horlick et al., 1991). However the data of Antonicelli et al. 2001 regarding sequences of the mouse Anxa1 promoter brought evidence of the involvement of the CREB transcription factor (the cyclic AMP-responding element-binding protein) in the activation of this gene by cyclic AMP and glucocorticoids.
Localisation ANXA1 is preferentially localized in the cytoplasm and associated with the plasma membrane or cytoskeleton, but it has also been localized outside the plasma membrane.
Function The function of the annexin A1 is far to be clear, it has been involved in signal transduction (Alldridge et al., 1999; de Coupade et al., 2000), vesicle transport (Diakonova et al., 1997), cell transformation (Violette et al., 1990; Solito et al., 1998a), inflammation (Perretti and Gavins, 2003), cell matrix interaction and apoptosis (Raynal and Pollard, 1994; Solito et al., 2001; Solito et al., 2003).
Homology The comparison of conserved and variable residues between human annexin 1 protein and annexin protein from different vertebrates shows amino acid identities of 100% (Pan troglodytes), 91% (Canis familiars), 87% (Mus musculus), 89% (Rattus norvegicus) and 77% (Gallus gallus) (Rodrigues-Lisoni et al., 2006).

Mutations

Note Reduced expression of ANXA1 could be explain by some mechanisms include gene deletions and mutations, hyper-methylation of the promoter with subsequent loss of transcription, and alterations in the post-translation processing (e.g. phosphorylation) of the protein involved in annexins regulation (de Coupade et al., 2000; Rodrigues-Lisoni et al., 2006; Alves et al., 2008).
Lindgren et al. (2001) studied subjects with type 2 diabetes and find a G instead of T at nucleotide position 362 from the transcription start site (exon 5) of ANXA1 gene in all individuals sequenced.

Implicated in

Entity Breast cancer
Disease In breast cancer, ANXA1 is believed to function as a tumor suppressor. In study with a tissue microarray using 82 pairs of primary breast cancers and lymph node metastases from archival materials the results revealed that ANXA1 expression was lost in 79% of breast carcinomas, and there was no difference in ANXA1 expression between primary breast carcinoma and lymph node metastasis (Cao et al., 2008).
Prognosis The suppressed ANXA1 expression in breast tissue is correlated with breast cancer development, progression and metastasis (Shen et al., 2006; Wang et al., 2010).
  
Entity Oral squamous cell carcinoma (OSCC)
Disease ANXA1 expression could be used as a suitable biomarker for patients with oral cavity cancer and its adoption for complementary non-invasive diagnosis of oral squamous cell carcinoma is suggested. Beyond the anti-inflammatory function, annexin A1 may also play a tumor suppressor role in peripheral blood cells (Faria et al., 2010).
Prognosis The nuclear localization of ANXA1 protein is a frequent event and could be used as a prognostic factor in OSCC (Lin et al., 2008).
  
Entity Laryngeal squamous cell carcinoma
Disease In surgical tissue specimens from 20 patients with laryngeal squamous cell carcinoma, ultrastructural immunocytochemistry analysis showed in vivo down-regulation of ANXA1 expression in the tumor and increased in mast cells and laryngeal squamous carcinoma cell line treated with ANXA1 peptide. Combined in vivo and in vitro analysis demonstrated that ANXA1 plays a regulatory role in laryngeal cancer cell growth (Silistino-Souza et al., 2007).
Prognosis ANXA1 dysregulation was observed early in laryngeal carcinogenesis, in intra-epithelial neoplasms (Alves et al., 2008).
  
Entity Lung squamous cell carcinoma
Disease The ANXA1 expression was identified by shot-gun proteomics strategy in lung squamous cell carcinoma.
Prognosis The ANXA1 might play an important role in lung squamous cell carcinoma genesis, progression, recurrence, and metastasis and might be used as markers of this carcinoma (Nan et al., 2009).
  
Entity Prostate cancer
Disease The reduction of ANXA1 expression, commonly associated with prostate cancer, could be due to elevated activity of histone deacetylases (D'Acunto et al., 2010) and interleukin 6 expression (Inokuchi et al., 2009).
Prognosis The ANXA1 expression is a contributing factor to the proapoptotic effects in prostate cancer (D'Acunto et al., 2010) and enhancing tumor aggressiveness via the upregulation of interleukin 6 expression and activity (Inokuchi et al., 2009).
  
Entity Leukaemia
Disease Immunocytochemical detection of ANXA1 represents a simple, inexpensive, highly sensitive and specific (100%) assay for diagnosis of hairy cell leukaemia. This assay will be especially useful in distinguishing hairy cell leukaemia from splenic lymphoma with villous lymphocytes and variant hairy cell leukaemia, both of which usually respond poorly to treatments that are effective in hairy cell leukaemia (Falini et al., 2004).
Prognosis The downregulated ANXA1 expression contributes considerably to the drug resistance in leukemia cell line (Zhu et al., 2009).
  
Entity Cervical cancer
Disease A close association was observed between ANXA1 expression and tumour cell differentiation in invasive squamous cell carcinoma.
Prognosis ANXA1 may be an effective candidate for detecting cervical intraephitelial neoplasia lesions and for evaluating tumour cell differentiation in squamous cell carcinoma of the cervix (Wang et al., 2008).
  
Entity Gastric cancer
Disease Loss of ANXA1 expression was significantly associated with advanced T stage, lymph node metastasis, advanced disease stage, and poor histological differentiation.
Prognosis ANXA1 expression decreased significantly as gastric cancer progressed and metastasized, suggesting the importance of ANXA1 as a negative biomarker for gastric cancer development and progression (Yu et al., 2008).
  
Entity Urinary bladder urothelial carcinoma
Disease Comparative proteomics and immunohistochemistry demonstrated that ANXA1 is up-regulated in high grade urinary bladder urothelial carcinoma as compared to non-high grade carcinomas.
Prognosis ANXA1 might be related to tumour progression. The ANXA1 overexpression and histological grade predicted disease-specific survival and metastasis-free survival (Li et al., 2010).
  
Entity Systemic lupus erythematosus
Disease Auto-antibodies against annexin A1 have been detected in patients with auto-immune diseases such as systemic lupus erythematosus (Hirata et al., 1981; Goulding et al., 1989).
  
Entity Rheumatoid arthritis
Disease ANXA1 has been recently shown to play a key role in T-cell activation and to be highly expressed in T cells from rheumatoid arthritis patients. Treatment of rheumatoid arthritis patients with steroid decreased ANXA1 expression in T cells.
Prognosis Steroids regulate the adaptive immune response and suggest that ANXA1 may represent a target for the treatment of autoimmune diseases (D'Acquisto et al., 2008).
  
Entity Crohn's disease
Disease Corticosteroids are widely used to treat patients with inflammatory bowel disease although the response is variable. Corticosteroids mediate some of their actions through ANXA1, and the induction of autoantibodies to ANXA1 has been proposed as a possible mechanism by which steroid efficacy is suboptimal in vivo (Beattie et al., 1995).
Prognosis The high levels of IgM ANXA1 antibodies in patients with Crohn's disease not taking corticosteroids provides further evidence of disturbed immunity in inflammatory bowel disease (Stevens et al., 1993).
  
Entity Cystic fibrosis
Disease Downregulation and degradation of ANXA1 was found in the bronchoalveolar lavage fluid of patients with cystic fibrosis indicating the susceptibility of these patients to lung inflammation. ANXA1 may be a key protein involved in cystic fibrosis pathogenesis especially in relation to the not well defined field of inflammation in cystic fibrosis (Tsao et al., 1998).
Prognosis Decreased expression of annexin A1 contributes to the worsening of the cystic fibrosis phenotype (Bensalem et al., 2005).
  
Entity Parkinson's disease
Disease ANXA1 expression has been linked to Parkinson's disease. ANXA1 immunoreactivity has been found in ameboid microglia within the astrocytic envelope of neurons adjacent to or within glial scars in the parkinsonian substantia nigra (Knott et al., 2000).
  
Entity Multiple sclerosis
Disease ANXA1 expression has been identified in the lesions of multiple sclerosis plaque and correlated with the degree of the disease (Probst-Cousin et al., 2002).
Prognosis Strategies aiming at reducing ANXA1 functions or expression in T cells might represent a novel therapeutic approach for multiple sclerosis (Paschalidis et al., 2009).
  

External links

Nomenclature
HGNC (Hugo)ANXA1   533
Cards
AtlasANXA1ID653ch9q21
Entrez_Gene (NCBI)ANXA1  301  annexin A1
GeneCards (Weizmann)ANXA1
Ensembl (Hinxton)ENSG00000135046 [Gene_View]  chr9:75766781-75785307 [Contig_View]  ANXA1 [Vega]
ICGC DataPortalENSG00000135046
AceView (NCBI)ANXA1
Genatlas (Paris)ANXA1
WikiGenes301
SOURCE (Princeton)NM_000700
Genomic and cartography
GoldenPath (UCSC)ANXA1  -  9q21.13   chr9:75766781-75785307 +  9q21.13   [Description]    (hg19-Feb_2009)
EnsemblANXA1 - 9q21.13 [CytoView]
Mapping of homologs : NCBIANXA1 [Mapview]
OMIM151690   
Gene and transcription
Genbank (Entrez)AB451274 AB451401 AK074480 AK296808 BC001275
RefSeq transcript (Entrez)NM_000700
RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NT_008470 NW_001839221 NW_004929366
Consensus coding sequences : CCDS (NCBI)ANXA1
Cluster EST : UnigeneHs.494173 [ NCBI ]
CGAP (NCI)Hs.494173
Alternative Splicing : Fast-db (Paris)GSHG0033543
Alternative Splicing GalleryENSG00000135046
Gene ExpressionANXA1 [ NCBI-GEO ]     ANXA1 [ SEEK ]   ANXA1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP04083 (Uniprot)
NextProtP04083  [Medical]
With graphics : InterProP04083
Splice isoforms : SwissVarP04083 (Swissvar)
Domaine pattern : Prosite (Expaxy)ANNEXIN (PS00223)   
Domains : Interpro (EBI)Annexin    Annexin_repeat    Annexin_repeat_CS    AnnexinI   
Related proteins : CluSTrP04083
Domain families : Pfam (Sanger)Annexin (PF00191)   
Domain families : Pfam (NCBI)pfam00191   
Domain families : Smart (EMBL)ANX (SM00335)  
DMDM Disease mutations301
Blocks (Seattle)P04083
PDB (SRS)1AIN    1BO9    1QLS   
PDB (PDBSum)1AIN    1BO9    1QLS   
PDB (IMB)1AIN    1BO9    1QLS   
PDB (RSDB)1AIN    1BO9    1QLS   
Human Protein AtlasENSG00000135046
Peptide AtlasP04083
HPRD01060
IPIIPI00218918   IPI00908577   IPI00549413   IPI00643231   
Protein Interaction databases
DIP (DOE-UCLA)P04083
IntAct (EBI)P04083
FunCoupENSG00000135046
BioGRIDANXA1
IntegromeDBANXA1
STRING (EMBL)ANXA1
Ontologies - Pathways
QuickGOP04083
Ontology : AmiGOcornified envelope  neutrophil homeostasis  negative regulation of acute inflammatory response  receptor binding  structural molecule activity  calcium ion binding  protein binding  phospholipid binding  calcium-dependent phospholipid binding  extracellular region  extracellular space  nucleus  cytoplasm  cytoplasm  plasma membrane  cilium  cellular component movement  inflammatory response  signal transduction  cell surface receptor signaling pathway  cell surface  response to X-ray  basolateral plasma membrane  peptide cross-linking  phospholipase A2 inhibitor activity  insulin secretion  keratinocyte differentiation  protein binding, bridging  endocrine pancreas development  positive regulation of vesicle fusion  positive regulation of prostaglandin biosynthetic process  mitochondrial membrane  response to estradiol  positive regulation of neutrophil apoptotic process  gliogenesis  regulation of cell proliferation  sarcolemma  response to drug  protein homodimerization activity  negative regulation of apoptotic process  negative regulation of catalytic activity  negative regulation of catalytic activity  protein complex  response to peptide hormone  alpha-beta T cell differentiation  calcium-dependent protein binding  arachidonic acid secretion  estrous cycle phase  extracellular vesicular exosome  cellular response to hydrogen peroxide  hepatocyte differentiation  response to interleukin-1  cellular response to glucocorticoid stimulus  neutrophil clearance  positive regulation of G1/S transition of mitotic cell cycle  negative regulation of interleukin-8 secretion  
Ontology : EGO-EBIcornified envelope  neutrophil homeostasis  negative regulation of acute inflammatory response  receptor binding  structural molecule activity  calcium ion binding  protein binding  phospholipid binding  calcium-dependent phospholipid binding  extracellular region  extracellular space  nucleus  cytoplasm  cytoplasm  plasma membrane  cilium  cellular component movement  inflammatory response  signal transduction  cell surface receptor signaling pathway  cell surface  response to X-ray  basolateral plasma membrane  peptide cross-linking  phospholipase A2 inhibitor activity  insulin secretion  keratinocyte differentiation  protein binding, bridging  endocrine pancreas development  positive regulation of vesicle fusion  positive regulation of prostaglandin biosynthetic process  mitochondrial membrane  response to estradiol  positive regulation of neutrophil apoptotic process  gliogenesis  regulation of cell proliferation  sarcolemma  response to drug  protein homodimerization activity  negative regulation of apoptotic process  negative regulation of catalytic activity  negative regulation of catalytic activity  protein complex  response to peptide hormone  alpha-beta T cell differentiation  calcium-dependent protein binding  arachidonic acid secretion  estrous cycle phase  extracellular vesicular exosome  cellular response to hydrogen peroxide  hepatocyte differentiation  response to interleukin-1  cellular response to glucocorticoid stimulus  neutrophil clearance  positive regulation of G1/S transition of mitotic cell cycle  negative regulation of interleukin-8 secretion  
Pathways : BIOCARTACorticosteroids and cardioprotection [Genes]   
REACTOMEP04083 [protein]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseANXA1
Wikipedia pathwaysANXA1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ANXA1
SNP (GeneSNP Utah)ANXA1
SNP : HGBaseANXA1
Genetic variants : HAPMAPANXA1
1000_GenomesANXA1 
ICGC programENSG00000135046 
CONAN: Copy Number AnalysisANXA1 
Somatic Mutations in Cancer : COSMICANXA1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)9:75766781-75785307
Mutations and Diseases : HGMDANXA1
OMIM151690   
MedgenANXA1
GENETestsANXA1
Disease Genetic AssociationANXA1
Huge Navigator ANXA1 [HugePedia]  ANXA1 [HugeCancerGEM]
Genomic VariantsANXA1  ANXA1 [DGVbeta]
Exome VariantANXA1
dbVarANXA1
ClinVarANXA1
snp3D : Map Gene to Disease301
DGIdb (Curated mutations)ANXA1
DGIdb (Drug Gene Interaction db)ANXA1
General knowledge
Homologs : HomoloGeneANXA1
Homology/Alignments : Family Browser (UCSC)ANXA1
Phylogenetic Trees/Animal Genes : TreeFamANXA1
Chemical/Protein Interactions : CTD301
Chemical/Pharm GKB GenePA24823
Clinical trialANXA1
Cancer Resource (Charite)ENSG00000135046
Other databases
Probes
Litterature
PubMed205 Pubmed reference(s) in Entrez
CoreMineANXA1
GoPubMedANXA1
iHOPANXA1

Bibliography

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Localization of five annexins in J774 macrophages and on isolated phagosomes.
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PMID 9191044
 
Human annexin 1 is highly expressed during the differentiation of the epithelial cell line A 549: involvement of nuclear factor interleukin 6 in phorbol ester induction of annexin 1.
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IL-6 stimulates annexin 1 expression and translocation and suggests a new biological role as class II acute phase protein.
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Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis.
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PMID 9448053
 
The annexin protein lipocortin 1 regulates the MAPK/ERK pathway.
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PMID 10608817
 
Annexin 1 expression and phosphorylation are upregulated during liver regeneration and transformation in antithrombin III SV40 T large antigen transgenic mice.
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PMID 10655260
 
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Characterization of the annexin I gene and evaluation of its role in type 2 diabetes.
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PMID 11574426
 
Transfection of annexin 1 in monocytic cells produces a high degree of spontaneous and stimulated apoptosis associated with caspase-3 activation.
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Annexins: from structure to function.
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Expression of annexin-1 in multiple sclerosis plaques.
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Neuropathol Appl Neurobiol. 2002 Aug;28(4):292-300.
PMID 12175341
 
Annexin 1: an endogenous anti-inflammatory protein.
Perretti M, Gavins FN.
News Physiol Sci. 2003 Apr;18:60-4. (REVIEW)
PMID 12644621
 
A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils.
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Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection of annexin A1 (ANXA1).
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Down-regulation of the anti-inflammatory protein annexin A1 in cystic fibrosis knock-out mice and patients.
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Annexin A1: from gene organization to physiology.
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Decreased expression of annexin A1 is correlated with breast cancer development and progression as determined by a tissue microarray analysis.
Shen D, Nooraie F, Elshimali Y, Lonsberry V, He J, Bose S, Chia D, Seligson D, Chang HR, Goodglick L.
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PMID 16949910
 
Annexin 1: differential expression in tumor and mast cells in human larynx cancer.
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PMID 17340616
 
Annexin A1 subcellular expression in laryngeal squamous cell carcinoma.
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PMID 19076685
 
Loss of annexin A1 expression in breast cancer progression.
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Glucocorticoid treatment inhibits annexin-1 expression in rheumatoid arthritis CD4+ T cells.
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PMID 18390587
 
Nuclear localization of annexin A1 is a prognostic factor in oral squamous cell carcinoma.
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PMID 18297688
 
Decreased expression of annexin A1 during the progression of cervical neoplasia.
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PMID 18652761
 
Tissue microarray analysis reveals strong clinical evidence for a close association between loss of annexin A1 expression and nodal metastasis in gastric cancer.
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PMID 18535914
 
Loss of annexin A1 disrupts normal prostate glandular structure by inducing autocrine IL-6 signaling.
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PMID 19351789
 
Analysis of the expression protein profiles of lung squamous carcinoma cell using shot-gun proteomics strategy.
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PMID 18988000
 
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PMID 20001861
 
Histone deacetylase inhibitor FR235222 sensitizes human prostate adenocarcinoma cells to apoptosis through up-regulation of Annexin A1.
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Cancer Lett. 2010 Mar 12. [Epub ahead of print]
PMID 20227822
 
Expression of annexin A1 mRNA in peripheral blood from oral squamous cell carcinoma patients.
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Oral Oncol. 2010 Jan;46(1):25-30. Epub 2009 Oct 14.
PMID 19833546
 
Annexin-I overexpression is associated with tumour progression and independently predicts inferior disease-specific and metastasis-free survival in urinary bladder urothelial carcinoma.
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Contributor(s)

Written05-2010Flavia Cristina Rodrigues-Lisoni, Tiago Henrique, Eloiza Helena Tajara
Department of Biology and Zootechny, Faculty of Engineering of Ilha Solteria (UNESP), Ilha Solteira, Brazil (FCRL); Department of Molecular Biology, School of Medicine (FAMERP), Sao Jose do Rio Preto, Brazil (TH, EHTDS)

Citation

This paper should be referenced as such :
Rodrigues-Lisoni, FC ; Henrique, T ; Tajara, EH
ANXA1 (annexin A1)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(2):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/ANXA1ID653ch9q21.html

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