Gene Summary

Gene:ANXA1; annexin A1
Aliases: ANX1, LPC1
Summary:This gene encodes a membrane-localized protein that binds phospholipids. This protein inhibits phospholipase A2 and has anti-inflammatory activity. Loss of function or expression of this gene has been detected in multiple tumors. [provided by RefSeq, Dec 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:annexin A1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (55)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • Bladder Cancer
  • Cell Movement
  • Tryptases
  • Chromosome 9
  • Reproducibility of Results
  • Proteomics
  • MicroRNAs
  • RNA Interference
  • Transforming Growth Factor beta
  • Neoplasm Invasiveness
  • Transcriptome
  • Annexin A1
  • Translocation
  • Tristetraprolin
  • Cell Proliferation
  • Messenger RNA
  • Gene Expression Profiling
  • Apoptosis
  • Squamous Cell Carcinoma
  • Stomach Cancer
  • Signal Transduction
  • RNA-Binding Proteins
  • Breast Cancer
  • Radiation Tolerance
  • MCF-7 Cells
  • Serine-Arginine Splicing Factors
  • Epithelial-Mesenchymal Transition
  • Sensitivity and Specificity
  • Risk Factors
  • ROC Curve
  • siRNA
  • Immunohistochemistry
  • Sequence Analysis, Protein
  • Oligonucleotide Array Sequence Analysis
  • Gene Expression
  • Survival Rate
  • Down-Regulation
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ANXA1 (cancer-related)

Zóia MAP, Azevedo FVP, Vecchi L, et al.
Inhibition of Triple-Negative Breast Cancer Cell Aggressiveness by Cathepsin D Blockage: Role of Annexin A1.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein, we reported that Annexin A1 (AnxA1) and Cathepsin D (CatD) are highly expressed in MDA-MB-231 (TNBC lineage), compared to MCF-10A and MCF-7. Since the proposed concept was that CatD has protumorigenic activity associated with its ability to cleave AnxA1 (generating a 35.5 KDa fragment), we investigated this mechanism more deeply using the inhibitor of CatD, Pepstatin A (PepA). Fourier Transform Infrared (FTIR) spectroscopy demonstrated that PepA inhibits CatD activity by occupying its active site; the OH bond from PepA interacts with a CO bond from carboxylic acids of CatD catalytic aspartate dyad, favoring the deprotonation of Asp

Pessolano E, Belvedere R, Bizzarro V, et al.
Annexin A1 May Induce Pancreatic Cancer Progression as a Key Player of Extracellular Vesicles Effects as Evidenced in the In Vitro MIA PaCa-2 Model System.
Int J Mol Sci. 2018; 19(12) [PubMed] Free Access to Full Article Related Publications
Pancreatic Cancer (PC) is one of the most aggressive malignancies worldwide. As annexin A1 (ANXA1) is implicated in the establishment of tumour metastasis, the role of the protein in PC progression as a component of extracellular vesicles (EVs) has been investigated. EVs were isolated from wild type (WT) and ANXA1 knock-out (KO) PC cells and then characterised by multiple approaches including Western blotting, Field Emission-Scanning Electron Microscopy, and Dynamic Light Scattering. The effects of ANXA1 on tumour aggressiveness were investigated by Wound-Healing and invasion assays and microscopic analysis of the Epithelial to Mesenchymal Transition (EMT). The role of ANXA1 on angiogenesis was also examined in endothelial cells, using similar approaches. We found that WT cells released more EVs enriched in exosomes than those from cells lacking ANXA1. Notably, ANXA1 KO cells recovered their metastatic potential only when treated by WT EVs as they underwent EMT and a significant increase of motility. Similarly, human umbilical vein endothelial cells (HUVEC) migrated and invaded more rapidly when treated by WT EVs whereas ANXA1 KO EVs weakly induced angiogenesis. This study suggests that EVs-related ANXA1 is able to promote cell migration, invasion, and angiogenesis, confirming the relevance of this protein in PC progression.

Yamanoi M, Yamanoi K, Fujii C, et al.
Annexin A1 expression is correlated with malignant potential of renal cell carcinoma.
Int J Urol. 2019; 26(2):284-290 [PubMed] Related Publications
OBJECTIVES: To evaluate the expression of annexin A1 protein in patients with renal cell carcinoma.
METHODS: Annexin A1 expression was examined in renal cell carcinoma specimens from 27 patients, and their disease-free survival was analyzed using the log-rank test. Annexin A1 knockdown in the human renal cell carcinoma cell line Caki-1 was carried out, and its proliferation, invasion, motility and adhesion were compared with those of control cells.
RESULTS: In 13 out of 27 patients, annexin A1 was highly expressed in the membrane of renal cell carcinoma tumor cells, whereas in the rest of the patients, annexin A1 expression was weak or negligible in the membrane of those cells. Patients with high annexin A1 expression had significantly poorer disease-free survival than those with weak or negligible annexin A1 expression (P = 0.031). In the renal cell carcinoma cell line, annexin A1 knockdown cells showed significantly decreased proliferation, invasion, motility and adhesion relative to control cells, and expressed lower relative levels of membrane-type 1 matrix metalloproteinase and hypoxia-inducible factor 1-alpha transcripts, showing a potential pathway regulated by annexin A1.
CONCLUSION: Annexin A1 is associated with renal cell carcinoma malignant potential and could serve as a marker of poor prognosis.

Han GH, Lu KJ, Huang JX, et al.
Association of serum annexin A1 with treatment response and prognosis in patients with esophageal squamous cell carcinoma.
J Cancer Res Ther. 2018; 14(Supplement):S667-S674 [PubMed] Related Publications
Objective: Annexin A1 (ANXA1), a calcium-dependent phospholipid binding protein, is known to be regulated by microRNA-196a (miR-196a) in esophageal adenocarcinoma, and its high expression in tumor tissue is correlated with the poor prognosis of esophageal squamous cell carcinoma (ESCC). However, the role of ANXA1 in the serum of patients with ESCC remains unclear.
Materials and Methods: In this study, we used enzyme-linked immunosorbent assay to evaluate the levels of ANXA1 and real-time polymerase chain reaction to detect the expression of miR-196a in the serum of ESCC patients (healthy donors as controls) and evaluated the relationship between ANXA1 and clinical outcomes.
Results: The results showed that the level of serum ANXA1 in ESCC patients was significantly lower than that in controls (P = 0.001) but increased after chemoradiotherapy (P = 0.001). There was no correlation between the baseline level of serum ANXA1 and the short-term efficacy of treatment (P = 0.26) as well as the 1-year progression-free survival (PFS) (P = 0.094). However, there existed a significant correlation between the increases of serum ANXA1 expression and the 1-year PFS (P = 0.04). A higher increase (>2-fold of baseline) in the serum ANXA1 levels was correlated with a poorer PFS (hazard ratio = 3.096, 95% confidence interval 1.239-7.861). There was an inverse correlation between the expressions of miR-196a and ANXA1 in serum (Pearson's correlation of -0.54, P = 0.021).
Conclusion: Our data revealed that the expression of serum ANXA1 in ESCC patients increases after chemoradiotherapy and the increased fold change in serum ANXA1 confers independent negative prognostic impact in ESCC. The higher the increase in serum ANXA1 levels, the poorer the outcome.

Raulf N, Lucarelli P, Thavaraj S, et al.
Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers.
Eur J Cancer. 2018; 102:52-68 [PubMed] Related Publications
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown. We have recently identified microRNA miR-196a to be highly overexpressed in HNSCC with poor prognosis. Oncogenic miR-196a directly targets Annexin A1 (ANXA1). Although increased ANXA1 expression levels have been associated with breast cancer development, its role in HNSCC is debatable and its functional contribution to HNSCC development remains unclear.
METHODS: ANXA1 mRNA and protein expression levels were determined by RNA Seq analysis and immunohistochemistry, respectively. Gain- and loss-of-function studies were performed to analyse the effects of ANXA1 modulation on cell proliferation, mechanism of activation of EGFR signalling as well as on exosome production and exosomal phospho-EGFR.
RESULTS: ANXA1 was found to be downregulated in head and neck cancer tissues, both at mRNA and protein level. Its anti-proliferative effects were mediated through the intracellular form of the protein. Importantly, ANXA1 downregulation resulted in increased phosphorylation and activity of EGFR and its downstream PI3K-AKT signalling. Additionally, ANXA1 modulation affected exosome production and influenced the release of exosomal phospho-EGFR.
CONCLUSIONS: ANXA1 acts as a tumour suppressor in HNSCC. It is involved in the regulation of EGFR activity and exosomal phospho-EGFR release and could be an important prognostic biomarker.

Li D, Hao X, Song Y
Identification of the Key MicroRNAs and the miRNA-mRNA Regulatory Pathways in Prostate Cancer by Bioinformatics Methods.
Biomed Res Int. 2018; 2018:6204128 [PubMed] Free Access to Full Article Related Publications
Objective: To identify key microRNAs (miRNAs) and their regulatory networks in prostate cancer.
Methods: Four miRNA and three gene expression microarray datasets were downloaded for analysis from Gene Expression Omnibus database. The differentially expressed miRNA and genes were accessed by a GEO2R. Functional and pathway enrichment analyses were performed using the DAVID program. Protein-protein interaction (PPI) and miRNA-mRNA regulatory networks were constructed using the STRING and Cytoscape tool. Moreover, the results and clinical significance were validated in TCGA data.
Results: We identified 26 significant DEMs, 633 upregulated DEGs, and 261 downregulated DEGs. Functional enrichment analysis indicated that significant DEGs were related to TGF-beta signaling pathway and TNF signaling pathway in PCa. Key DEGs such as HSPA8, PPP2R1A, CTNNB1, ADCY5, ANXA1, and COL9A2 were found as hub genes in PPI networks. TCGA data supported our results and the miRNAs were correlated with clinical stages and overall survival.
Conclusions: We identified 26 miRNAs that may take part in key pathways like TGF-beta and TNF pathways in prostate cancer regulatory networks. MicroRNAs like miR-23b, miR-95, miR-143, and miR-183 can be utilized in assisting the diagnosis and prognosis of prostate cancer as biomarkers. Further experimental studies are required to validate our results.

Belvedere R, Saggese P, Pessolano E, et al.
miR-196a Is Able to Restore the Aggressive Phenotype of Annexin A1 Knock-Out in Pancreatic Cancer Cells by CRISPR/Cas9 Genome Editing.
Int J Mol Sci. 2018; 19(7) [PubMed] Free Access to Full Article Related Publications
Annexin A1 (ANXA1) is a Ca

Vecchi L, Alves Pereira Zóia M, Goss Santos T, et al.
Inhibition of the AnxA1/FPR1 autocrine axis reduces MDA-MB-231 breast cancer cell growth and aggressiveness in vitro and in vivo.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(9):1368-1382 [PubMed] Related Publications
Breast Cancer (BC) is a highly heterogeneous disease whose most aggressive behavior is displayed by triple-negative breast cancer (TNBC), which lacks an efficient targeted therapy. Despite its controversial role, one of the proteins that having been linked with BC is Annexin A1 (AnxA1), which is a Ca

Xie H, Xue YQ, Liu P, et al.
Multi-parameter gene expression profiling of peripheral blood for early detection of hepatocellular carcinoma.
World J Gastroenterol. 2018; 24(3):371-378 [PubMed] Free Access to Full Article Related Publications
AIM: In our previous study, we have built a nine-gene (
METHODS: Logistic regression analysis, discriminant analysis, classification tree analysis, and artificial neural network were used for the multi-parameter gene expression analysis method. One hundred and three patients with early HCC and 54 age-matched healthy normal controls were used to build a diagnostic model. Fifty-two patients with early HCC and 34 healthy people were used for validation. The area under the curve, sensitivity, and specificity were used as diagnostic indicators.
RESULTS: Artificial neural network of the total nine genes had the best diagnostic value, and the AUC, sensitivity, and specificity were 0.943, 98%, and 85%, respectively. At last, 52 HCC patients and 34 healthy normal controls were used for validation. The sensitivity and specificity were 96% and 86%, respectively.
CONCLUSION: Multi-parameter analysis methods may increase the diagnostic value compared to single factor analysis and they may be a trend of the clinical diagnosis in the future.

Kopp S, Sahana J, Islam T, et al.
The role of NFκB in spheroid formation of human breast cancer cells cultured on the Random Positioning Machine.
Sci Rep. 2018; 8(1):921 [PubMed] Free Access to Full Article Related Publications
Human MCF-7 breast cancer cells were exposed to a Random Positioning Machine (RPM). After 24 hours (h) the cells grew either adherently within a monolayer (AD) or within multicellular spheroids (MCS). AD and MCS populations were separately harvested, their cellular differences were determined performing qPCR on genes, which were differently expressed in AD and MCS cells. Gene array technology was applied to detect RPM-sensitive genes in MCF-7 cells after 24 h. Furthermore, the capability to form multicellular spheroids in vitro was compared with the intracellular distribution of NF-kappaB (NFκB) p65. NFκB was equally distributed in static control cells, but predominantly localized in the cytoplasm in AD cells and nucleus in MCS cells exposed to the RPM. Gene array analyses revealed a more than 2-fold change of only 23 genes including some whose products are affected by oxygen levels or regulate glycolysis. Significant upregulations of the mRNAs of enzymes degrading heme, of ANXA1, ANXA2, CTGF, CAV2 and ICAM1, as well as of FAS, Casp8, BAX, p53, CYC1 and PARP1 were observed in MCS cells as compared with 1g-control and AD cells. An interaction analysis of 47 investigated genes suggested that HMOX-1 and NFκB variants are activated, when multicellular spheroids are formed.

Privat M, Rudewicz J, Sonnier N, et al.
Antioxydation And Cell Migration Genes Are Identified as Potential Therapeutic Targets in Basal-Like and BRCA1 Mutated Breast Cancer Cell Lines.
Int J Med Sci. 2018; 15(1):46-58 [PubMed] Free Access to Full Article Related Publications
Basal-like breast cancers are among the most aggressive cancers and effective targeted therapies are still missing. In order to identify new therapeutic targets, we performed Methyl-Seq and RNA-Seq of 10 breast cancer cell lines with different phenotypes. We confirmed that breast cancer subtypes cluster the RNA-Seq data but not the Methyl-Seq data. Basal-like tumor hypermethylated phenotype was not confirmed in our study but RNA-Seq analysis allowed to identify 77 genes significantly overexpressed in basal-like breast cancer cell lines. Among them, 48 were overexpressed in triple negative breast cancers of TCGA data. Some molecular functions were overrepresented in this candidate gene list. Genes involved in antioxydation, such as SOD1, MGST3 and PRDX or cadherin-binding genes, such as PFN1, ITGB1 and ANXA1, could thus be considered as basal like breast cancer biomarkers. We then sought if these genes were linked to BRCA1, since this gene is often inactivated in basal-like breast cancers. Nine genes were identified overexpressed in both basal-like breast cancer cells and BRCA1 mutated cells. Amongst them, at least 3 genes code for proteins implicated in epithelial cell migration and epithelial to mesenchymal transition (VIM, ITGB1 and RhoA). Our study provided several potential therapeutic targets for triple negative and BRCA1 mutated breast cancers. It seems that migration and mesenchymal properties acquisition of basal-like breast cancer cells is a key functional pathway in these tumors with a high metastatic potential.

Fawzy MS, Toraih EA, Ibrahiem A, et al.
Evaluation of miRNA-196a2 and apoptosis-related target genes: ANXA1, DFFA and PDCD4 expression in gastrointestinal cancer patients: A pilot study.
PLoS One. 2017; 12(11):e0187310 [PubMed] Free Access to Full Article Related Publications
Previous reports have suggested the significant association of miRNAs aberrant expression with tumor initiation, progression and metastasis in cancer, including gastrointestinal (GI) cancers. The current preliminary study aimed to evaluate the relative expression levels of miR-196a2 and three of its selected apoptosis-related targets; ANXA1, DFFA and PDCD4 in a sample of GI cancer patients. Quantitative real-time PCR for miR-196a2 and its selected mRNA targets, as well as immunohistochemical assay for annexin A1 protein expression were detected in 58 tissues with different GI cancer samples. In addition, correlation with the clinicopathological features and in silico network analysis of the selected molecular markers were analyzed. Stratified analyses by cancer site revealed elevated levels of miR-196a2 and low expression of the selected target genes. Annexin protein expression was positively correlated with its gene expression profile. In colorectal cancer, miR-196a over-expression was negatively correlated with annexin A1 protein expression (r = -0.738, p < 0.001), and both were indicators of unfavorable prognosis in terms of poor differentiation, larger tumor size, and advanced clinical stage. Taken together, aberrant expression of miR-196a2 and the selected apoptosis-related biomarkers might be involved in GI cancer development and progression and could have potential diagnostic and prognostic roles in these types of cancer; particularly colorectal cancer, provided the results experimentally validated and confirmed in larger multi-center studies.

Chen L, Yuan Y, Kar S, et al.
PPARγ Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers.
Mol Cancer Ther. 2017; 16(11):2528-2542 [PubMed] Related Publications
Metastatic breast cancer is still incurable so far; new specifically targeted and more effective therapies for triple-negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPARγ. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show

Xu Y, Wang J, Xu Y, et al.
Screening critical genes associated with malignant glioma using bioinformatics analysis.
Mol Med Rep. 2017; 16(5):6580-6589 [PubMed] Free Access to Full Article Related Publications
Malignant gliomas are high‑grade gliomas, which are derived from glial cells in the spine or brain. To examine the mechanisms underlying malignant gliomas in the present study, the expression profile of GSE54004, which included 12 grade II astrocytomas, 33 grade III astrocytomas and 98 grade IV astrocytomas, was downloaded from the Gene Expression Omnibus. Using the Limma package in R, the differentially expressed genes (DEGs) in grade III, vs. grade II astrocytoma, grade IV, vs. grade II astrocytoma, and grade IV, vs. grade III astrocytoma were analyzed. Venn diagram analysis and enrichment analyses were performed separately for the DEGs using VennPlex software and the Database for Annotation, Visualization and Integrated Discovery. Protein‑protein interaction (PPI) networks were visualized using Cytoscape software, and subsequent module analysis of the PPI networks was performed using the ClusterONE tool. Finally, glioma‑associated genes and glioma marker genes among the DEGs were identified using the CTD database. A total of 27, 1,446 and 776 DEGs were screened for the grade III, vs. grade II, grade IV, vs. grade II, and grade IV, vs. grade III astrocytoma comparison groups, respectively. Functional enrichment analyses showed that matrix metalloproteinase 9 (MMP9) and chitinase 3‑like 1 (CHI3L1) were enriched in the extracellular matrix and extracellular matrix structural constituent, respectively. In the PPI networks, annexin A1 (ANXA1) had a higher degree and MMP9 had interactions with vascular endothelial growth factor A (VEGFA). There were 10 common glioma marker genes between the grade IV, vs. grade II and the grade IV, vs. grade III comparison groups, including MMP9, CHI3L1, VEGFA and S100 calcium binding protein A4 (S100A4). This suggested that MMP9, CHI3L1, VEGFA, S100A4 and ANXA1 may be involved in the progression of malignant gliomas.

Álvarez-Teijeiro S, Menéndez ST, Villaronga MÁ, et al.
Annexin A1 down-regulation in head and neck squamous cell carcinoma is mediated via transcriptional control with direct involvement of miR-196a/b.
Sci Rep. 2017; 7(1):6790 [PubMed] Free Access to Full Article Related Publications
Annexin A1 (ANXA1) down-regulation is an early and frequent event in the development of head and neck squamous cell carcinomas (HNSCC). In an attempt to identify the underlying mechanisms of reduced ANXA1 protein expression, this study investigated ANXA1 mRNA expression in HNSCC specimens by both in situ hybridization and RT-qPCR. Results showed a perfect concordance between the pattern of ANXA1 mRNA and protein detected by immunofluorescence in tumors, precancerous lesions and normal epithelia, reflecting that ANXA1 down-regulation occurs at transcriptional level. We also found that both miR-196a and miR-196b levels inversely correlated with ANXA1 mRNA levels in paired HNSCC tissue samples and patient-matched normal mucosa. In addition, endogenous levels of ANXA1 mRNA and protein were consistently and significantly down-regulated upon miR-196a and miR-196b over-expression in various HNSCC-derived cell lines. The direct interaction of both mature miR-196a and miR-196b was further confirmed by transfection with Anxa1 3'UTR constructs. Combined bioinformatics and functional analysis of ANXA1 promoter activity contributed to identify key regions and potential mediators of ANXA1 transcriptional control. This study unveils that, in addition to miR-196a, miR-196b also directly targets ANXA1 in HNSCC.

De Luca L, Trino S, Laurenzana I, et al.
Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia.
Cell Death Dis. 2017; 8(6):e2849 [PubMed] Free Access to Full Article Related Publications
Lin28A is a highly conserved RNA-binding protein that concurs to control the balance between stemness and differentiation in several tissue lineages. Here, we report the role of miR-128a/Lin28A axis in blocking cell differentiation in acute myeloid leukemia (AML), a genetically heterogeneous disease characterized by abnormally controlled proliferation of myeloid progenitor cells accompanied by partial or total inability to undergo terminal differentiation. First, we found Lin28A underexpressed in blast cells from AML patients and AML cell lines as compared with CD34+ normal precursors. In vitro transfection of Lin28A in NPM1-mutated OCI-AML3 cell line significantly triggered cell-cycle arrest and myeloid differentiation, with increased expression of macrophage associate genes (EGR2, ZFP36 and ANXA1). Furthermore, miR-128a, a negative regulator of Lin28A, was found overexpressed in AML cells compared with normal precursors, especially in acute promyelocytic leukemia (APL) and in 'AML with maturation' (according to 2016 WHO classification of myeloid neoplasms and acute leukemia). Its forced overexpression by lentiviral infection in OCI-AML3 downregulated Lin28A with ensuing repression of macrophage-oriented differentiation. Finally, knockdown of miR-128a in OCI-AML3 and in APL/AML leukemic cells (by transfection and lentiviral infection, respectively) induced myeloid cell differentiation and increased expression of Lin28A, EGR2, ZFP36 and ANXA1, reverting myeloid differentiation blockage. In conclusion, our findings revealed a new mechanism for AML differentiation blockage, suggesting new strategies for AML therapy based upon miR-128a inhibition.

Rossi A, Moro A, Tebaldi T, et al.
Identification and dynamic changes of RNAs isolated from RALY-containing ribonucleoprotein complexes.
Nucleic Acids Res. 2017; 45(11):6775-6792 [PubMed] Free Access to Full Article Related Publications
RALY is a member of the heterogeneous nuclear ribonucleoprotein family (hnRNP), a large family of RNA-binding proteins involved in many aspects of RNA metabolism. Although RALY interactome has been recently characterized, a comprehensive global analysis of RALY-associated RNAs is lacking and the biological function of RALY remains elusive. Here, we performed RIP-seq analysis to identify RALY interacting RNAs and assessed the role of RALY in gene expression. We demonstrate that RALY binds specific coding and non-coding RNAs and associates with translating mRNAs of mammalian cells. Among the identified transcripts, we focused on ANXA1 and H1FX mRNAs, encoding for Annexin A1 and for the linker variant of the histone H1X, respectively. Both proteins are differentially expressed by proliferating cells and are considered as markers for tumorigenesis. We demonstrate that cells lacking RALY expression exhibit changes in the levels of H1FX and ANXA1 mRNAs and proteins in an opposite manner. We also provide evidence for a direct binding of RALY to the U-rich elements present within the 3΄UTR of both transcripts. Thus, our results identify RALY as a poly-U binding protein and as a regulator of H1FX and ANXA1 in mammalian cells.

Procházková I, Lenčo J, Fučíková A, et al.
Targeted proteomics driven verification of biomarker candidates associated with breast cancer aggressiveness.
Biochim Biophys Acta Proteins Proteom. 2017; 1865(5):488-498 [PubMed] Related Publications
Breast cancer is the most common and molecularly relatively well characterized malignant disease in women, however, its progression to metastatic cancer remains lethal for 78% of patients 5years after diagnosis. Novel markers could identify the high risk patients and their verification using quantitative methods is essential to overcome genetic, inter-tumor and intra-tumor variability and translate novel findings into cancer diagnosis and treatment. We recently identified 13 proteins associated with estrogen receptor, tumor grade and lymph node status, the key factors of breast cancer aggressiveness, using untargeted proteomics. Here we verified these findings in the same set of 96 tumors using targeted proteomics based on selected reaction monitoring with mTRAQ labeling (mTRAQ-SRM), transcriptomics and immunohistochemistry and validated in 5 independent sets of 715 patients using transcriptomics. We confirmed: (i) positive association of anterior gradient protein 2 homolog (AGR2) and periostin (POSTN) and negative association of annexin A1 (ANXA1) with estrogen receptor status; (ii) positive association of stathmin (STMN1), cofilin-1 (COF1), plasminogen activator inhibitor 1 RNA-binding protein (PAIRBP1) and negative associations of thrombospondin-2 (TSP2) and POSTN levels with tumor grade; and (iii) positive association of POSTN, alpha-actinin-4 (ACTN4) and STMN1 with lymph node status. This study highlights a panel of gene products that can contribute to breast cancer aggressiveness and metastasis, the understanding of which is important for development of more precise breast cancer treatment.

Shen L, Zhao L, Tang J, et al.
Key Genes in Stomach Adenocarcinoma Identified via Network Analysis of RNA-Seq Data.
Pathol Oncol Res. 2017; 23(4):745-752 [PubMed] Related Publications
RNA-seq data of stomach adenocarcinoma (STAD) were analyzed to identify critical genes in STAD. Meanwhile, relevant small molecule drugs, transcription factors (TFs) and microRNAs (miRNAs) were also investigated. Gene expression data of STAD were downloaded from The Cancer Genome Atlas (TCGA). Differential analysis was performed with package edgeR. Relationships with correlation coefficient > 0.6 were retained in the gene co-expression network. Functional enrichment analysis was performed for the genes in the network with DAVID and KOBASS 2.0. Modules were identified using Cytoscape. Relevant small molecules drugs, transcription factors (TFs) and microRNAs (miRNAs) were revealed by using CMAP and WebGestalt databases. A total of 520 DEGs were identified between 285 STAD samples and 33 normal controls, including 244 up-regulated and 276 down-regulated genes. A gene co-expression network containing 53 DEGs and 338 edges was constructed, the genes of which were significantly enriched in focal adhesion, ECM-receptor interaction and vascular smooth muscle contraction pathways. Three modules were identified from the gene co-expression network and they were associated with skeletal system development, inflammatory response and positive regulation of cellular process, respectively. A total of 20 drugs, 9 TFs and 6 miRNAs were acquired that may regulate the DEGs. NFAT-COL1A1/ANXA1, HSF2-FOS, SREBP-IL1RN and miR-26-COL5A2 regulation axes may be important mechanisms for STAD.

Han G, Lu K, Huang J, et al.
Effect of Annexin A1 gene on the proliferation and invasion of esophageal squamous cell carcinoma cells and its regulatory mechanisms.
Int J Mol Med. 2017; 39(2):357-363 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to examine the effect of Annexin A1 (ANXA1) on the proliferation, migration and invasion of esophageal squamous cell carcinoma (ESCC) cells and its possible mechanisms of action. After constructing the ANXA1 overexpression plasmid, we transfected this plasmid and/or microRNA (miRNA)‑196a mimic into ESCC cells (Eca109 cell line). Methyl thiazolyl tetrazolium (MTT) assay and Transwell chamber assay were performed to determine cell proliferation, migration and invasion, respectively. Western blot analysis was used to examine the protein expression levels of ANXA1, Snail and E-cadherin. RT-PCR was used to detect the expression of miRNA-196a. Our results revealed that ANXA1 expression was upregulated in the cells transfected with the ANXA1 overexpression plasmid, and cell proliferation, migration and invasion were significantly increased (p=0.004, p<0.001 and p=0.011, respectively). In the cells transfected with the miRNA‑196a mimic, miRNA‑196a expression was significantly upregulated (p<0.001). However, miRNA-196a expression was downregulated in the cells transfected with the ANXA1 overexpression plasmid. In addition, in the cells transfected with the miRNA‑196a mimic, cell proliferation, migration and invasion were significantly decreased (p=0.027, p=0.009 and p=0.021, respectively). In the cells transfected with the ANXA1 overexpression plasmid, the expression of Snail was upregulated and that of E-cadherin was downregulated. However, the opposite was observed in the cells transfected with the miRNA‑196a mimic. Our findings thus demonstrate that ANXA1 promotes the proliferation of Eca109 cells, and increases the expression of Snail, whereas it inhibits that of E-cadherin, thus enhancing the migration and invasion of ESCC cells. miRNA-196a negatively regulates the expression of ANXA1, thereby inhibiting the proliferation, invasion and metastasis of ESCC cells.

Wang X, Zhi Q, Liu S, et al.
Identification of specific biomarkers for gastric adenocarcinoma by ITRAQ proteomic approach.
Sci Rep. 2016; 6:38871 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to identify biomarkers for gastric cancer (GC) by iTRAQ. Using proteins extracted from a panel of 4 pairs of gastric adenocarcinoma samples (stage III-IV, Her-2 negative), we identified 10 up regulated and 9 down regulated proteins in all four pairs of GC samples compared to adjacent normal gastric tissue. The up regulated proteins are mainly involved in cell motility, while the down regulated proteins are mitochondrial enzymes involved in energy metabolism. The expression of three up regulated proteins (ANXA1, NNMT, fibulin-5) and one of the down regulated proteins (UQCRC1) was validated by Western Blot in 97 GC samples. ANXA1 was up regulated in 61.36% of stage I/II GC samples compared to matched adjacent normal gastric tissue, and its expression increased further in stage III/IV samples. Knockdown of ANXA1 by siRNA significantly inhibited GC cell migration and invasion, whereas over expression of ANXA1 promoted migration and invasion. We found decreased expression of UQCRC1 in all stages of GC samples. Our data suggest that increased cell motility and decreased mitochondrial energy metabolism are important hallmarks during the development of GC.

Onozawa H, Saito M, Saito K, et al.
Annexin A1 is involved in resistance to 5-FU in colon cancer cells.
Oncol Rep. 2017; 37(1):235-240 [PubMed] Related Publications
Resistance to 5-fluorouracil (5‑FU), a key drug in the treatment of colorectal cancer, is one of the major reasons for poor patient prognosis during cancer treatment. Annexin A1 (ANXA1) is a calcium‑dependent phospholipid‑linked protein that is associated with drug resistance, anti‑inflammatory effects, regulation of cellular differentiation, proliferation and apoptosis. Although there have been several studies investigating ANXA1 expression in drug resistant cells, the role of ANXA1 is yet to be fully understood. We therefore, in this study, generated SW480 cells resistant to 5‑FU (SW480/5‑FU) to evaluate ANXA1 expression. When compared to the control cells, ANXA1 expression was significantly induced in the SW480/5‑FU cells. We then revealed the role of ANXA1 expression in 5‑FU resistance by using overexpression and knockdown methods in colon cancer cells. Overexpression of ANXA1 induced a significant increase of cell viability to 5‑FU, whereas ANXA1 knockdown induced a significant decrease of cell viability to 5‑FU. Further experiments revealed that ANXA1 expression was induced by hypoxia in colon cancer cells. These results suggest that ANXA1 expression may play a critical role in 5‑FU resistance and may be induced by hypoxia during cancer progression. Our results provide a possible strategy to overcome 5‑FU resistance by modulating ANXA1 expression.

Bizzarro V, Belvedere R, Migliaro V, et al.
Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness.
Cell Adh Migr. 2017; 11(3):247-260 [PubMed] Free Access to Full Article Related Publications
Annexin A1 (ANXA1) is a Ca

Berns K, Sonnenblick A, Gennissen A, et al.
Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance.
Clin Cancer Res. 2016; 22(21):5238-5248 [PubMed] Related Publications
PURPOSE: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment.
EXPERIMENTAL DESIGN: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2
RESULTS: We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2
CONCLUSIONS: Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression. Clin Cancer Res; 22(21); 5238-48. ©2016 AACR.

Shin J, Song IS, Pak JH, Jang SW
Upregulation of annexin A1 expression by butyrate in human melanoma cells induces invasion by inhibiting E-cadherin expression.
Tumour Biol. 2016; 37(11):14577-14584 [PubMed] Related Publications
Epithelial to mesenchymal transition (EMT) is a critical step in the metastasis of epithelial cancer cells. Butyrate, which is produced from dietary fiber by colonic bacterial fermentation, has been reported to influence EMT. However, some studies have reported that butyrate promotes EMT, while others have reported an inhibitory effect. To clarify these controversial results, it is necessary to elucidate the mechanism by which butyrate can influence EMT. In this study, we examined the potential role of annexin A1 (ANXA1), which was previously reported to promote EMT in breast cancer cells, as a mediator of EMT regulation by butyrate. We found that ANXA1 mRNA and protein were expressed in highly invasive melanoma cell lines (A2058 and A375), but not in SK-MEL-5 cells, which are less invasive. We also showed that butyrate induced ANXA1 mRNA and protein expression and promoted EMT-related cell invasion in SK-MEL-5 cells. Downregulation of ANXA1 expression using specific small interfering RNAs in butyrate-treated SK-MEL-5 cells resulted in increased expression of the epithelial marker E-cadherin and decreased cell invasion. Moreover, overexpressing ANXA1 decreased the expression of the E-cadherin. Collectively, these results indicate that butyrate induces the expression of ANXA1 in human melanoma cells, which then promotes invasion through activating the EMT signaling pathway.

Ries M, Loiola R, Shah UN, et al.
The anti-inflammatory Annexin A1 induces the clearance and degradation of the amyloid-β peptide.
J Neuroinflammation. 2016; 13(1):234 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The toxicity of amyloid-β (Aβ) peptide present in the brain of Alzheimer's disease (AD) patients is thought to be mediated via the increased secretion of pro-inflammatory mediators, which can lead to neuronal dysfunction and cell death. In addition, we have previously shown that inflammation can affect Aβ generation. More recently, we have reported that in vitro administration of the anti-inflammatory mediator Annexin A1 (ANXA1) following an inflammatory challenge suppressed microglial activation and this effect was mediated through formyl peptide receptor-like 1 (FPRL1/FPR2) signalling. The aim of this study was to determine the potential role of ANXA1 in the generation and clearance of Aβ.
METHODS: We first compared ANXA1 protein expression in the brains of AD patients and healthy controls as well as in the 5XFAD model of AD. To determine the role of ANXA1 in the processing of amyloid precursor protein (APP) and the degradation of Aβ, N2a neuroblastoma cells were treated with human recombinant ANXA1 or transfected with ANXA1 siRNA. We also investigated the effect of ANXA1 on Aβ phagocytosis and microglial activation in BV2 cells treated with synthetic Aβ.
RESULTS: Our data show that ANXA1 is increased in the brains of AD patients and animal models of AD at early stages. ANXA1 was able to reduce the levels of Aβ by increasing its enzymatic degradation by neprilysin in N2a cells and to stimulate Aβ phagocytosis by microglia. These effects were mediated through FPRL1 receptors. In addition, ANXA1 inhibited the Aβ-stimulated secretion of inflammatory mediators by microglia.
CONCLUSIONS: These data suggest that ANXA1 plays a pivotal role in Aβ clearance and supports the use of ANXA1 as potential pharmacological tool for AD therapeutics.

Calmon MF, Sichero L, Boccardo E, et al.
HPV16 E6 regulates annexin 1 (ANXA1) protein expression in cervical carcinoma cell lines.
Virology. 2016; 496:35-41 [PubMed] Related Publications
Annexin 1 (ANXA1) is a substrate for E6AP mediated ubiquitylation. It has been hypothesized that HPV 16 E6 protein redirects E6AP away from ANXA1, increasing its stability and possibly contributing to viral pathogenesis. We analyzed ANXA1 expression in HPV-positive and negative cervical carcinoma-derived cells, in cells expressing HPV-16 oncogenes and in cells transduced with shRNA targeting E6AP. We observed that ANXA1 protein expression increased in HPV-16-positive tumor cells, in keratinocytes expressing HPV-16 E6wt (wild-type) or E6/E7 and C33 cells expressing HPV-16 E6wt. ANXA1 protein expression decreased in cells transfected with E6 Dicer-substrate RNAs (DsiRNA) and C33 cells cotransduced with HPV-16 E6wt and E6AP shRNA. Moreover, colony number and proliferation rate decreased in HPV16-positive cells transduced with ANXA1 shRNA. We observed that in cells infected with HPV16, the E6 binds to E6AP to degrade p53 and upregulate ANXA1. We suggest that ANXA1 may play a role in HPV-mediated carcinogenesis.

Franco-Salla GB, Prates J, Cardin LT, et al.
Euphorbia tirucalli modulates gene expression in larynx squamous cell carcinoma.
BMC Complement Altern Med. 2016; 16:136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Some plants had been used in the treatment of cancer and one of these has attracted scientific interest, the Euphorbia tirucalli (E. tirucalli), used in the treatment of asthma, ulcers, warts has active components with activities scientifically proven as antimutagenic, anti-inflammatory and anticancer.
METHODS: We evaluate the influence of the antitumoral fraction of the E. tirucalli latex in the larynx squamous cell carcinoma (Hep-2), on the morphology, cell proliferation and gene expression. The Hep-2 cells were cultivated in complete medium (MEM 10 %) and treated with E. tirucalli latex for 1, 3, 5 and 7 days. After statistically analyzing the proliferation of the tested cells, the cells were cultivated again for RNA extraction and the Rapid Subtractive Hybridization (RaSH) technique was used to identify genes with altered expression. The genes found using the RaSH technique were analyzed by Gene Ontology (GO) using Ingenuity Systems.
RESULTS: The five genes found to have differential expression were validated by real-time quantitative PCR. Though treatment with E. tirucalli latex did not change the cell morphology in comparison to control samples, but the cell growth was significantly decreased. The RaSH showed change in the expression of some genes, including ANXA1, TCEA1, NGFRAP1, ITPR1 and CD55, which are associated with inflammatory response, transcriptional regulation, apoptosis, calcium ion transport regulation and complement system, respectively. The E. tirucalli latex treatment down-regulated ITPR1 and up-regulated ANXA1 and CD55 genes, and was validated by real-time quantitative PCR.
CONCLUSIONS: The data indicate the involvement of E. tirucalli latex in the altered expression of genes involved in tumorigenic processes, which could potentially be applied as a therapeutic indicator of larynx cancer.

Yuan Y, Anbalagan D, Lee LH, et al.
ANXA1 inhibits miRNA-196a in a negative feedback loop through NF-kB and c-Myc to reduce breast cancer proliferation.
Oncotarget. 2016; 7(19):27007-20 [PubMed] Free Access to Full Article Related Publications
MiRNAs are endogenous ~22 nt RNAs which play critical regulatory roles in a wide range of biological and pathological processes, which can act as oncogenes or tumor suppressor genes depending on their target genes. We have recently shown that ANXA1 inhibits the expression of miRNAs including miR196a. Here, we show that miR196a was highly expressed in ER+ MCF-7 breast cancer cells when compared to normal mammary gland cells, with expression levels negatively correlating to ANXA1. ANXA1 inhibits the biogenesis of oncogenic miR-196a by suppressing primary-miR196a indirectly through the stimulation of c-myc and NFkB expression and activity in breast cancer cells. In a negative feedback loop, miR-196a directly inhibits ANXA1 and enhances breast cancer cell proliferation in vitro. Finally, miR196a promotes breast tumor growth in vivo. This study reports a novel regulatory circuit between ANXA1, NF-kB, c-myc and miR-196a which regulates breast cancer cell proliferation and tumor growth.

Fang Y, Guan X, Cai T, et al.
Knockdown of ANXA1 suppresses the biological behavior of human NSCLC cells in vitro.
Mol Med Rep. 2016; 13(5):3858-66 [PubMed] Free Access to Full Article Related Publications
Annexin A1 (ANXA1) is a member of the annexin superfamily. Previous studies have reported that ANXA1 is highly expressed in various types of malignant tumor; however, its role in the progression of non‑small cell lung cancer (NSCLC) remains to be fully clarified. The present study aimed to investigate the oncogenic role of ANXA1 in NSCLC cells in vitro. RNA interference was used to downregulate ANXA1 expression in A549 and H1299 cells using a small interfering RNA lentiviral vector. Subsequently, cell proliferation and migration were detected using Cell Counting kit‑8, clone formation, wound healing and Transwell chamber assays. Successful transfection was confirmed using fluorescence microscopy, which demonstrated that ANXA1 had been efficiently inhibited. ANXA1 knockdown suppressed the proliferation, migration and invasion of NSCLC cells. In conclusion, the present study provided evidence suggesting that ANXA1 may contribute to the growth and invasion of NSCLC cell lines, and ANXA1 may be exploited as an in vitro therapeutic target for the treatment of NSCLC.

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