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Anxa1

Official Full Name
annexin A1
Background
Annexin I belongs to a family of Ca(2+)-dependent phospholipid binding proteins which have a molecular weight of approximately 35,000 to 40,000 and are preferentially located on the cytosolic face of the plasma membrane. Annexin I protein has an apparent relative molecular mass of 40 kDa, with phospholipase A2 inhibitory activity. Since phospholipase A2 is required for the biosynthesis of the potent mediators of inflammation, prostaglandins and leukotrienes, annexin I may have potential anti-inflammatory activity. [provided by RefSeq, Jul 2008]
Synonyms
ANXA1; annexin A1; ANX1; LPC1; p35; annexin-1; calpactin-2; calpactin II; lipocortin I; chromobindin-9; annexin I (lipocortin I); phospholipase A2 inhibitory protein; ANX1, LPC1; annexin I; calcium-dependent membrane binding protein annexin I

Annexin A1 (ANXA1) belongs to the first discovered protein in the Annexis family and was originally thought to be a glucocorticoid-regulated phospholipase A2 inhibitory protein. It is subsequently thought that stress proteins play a role in proliferation, differentiation, and apoptosis. In recent years, some studies of ANXA1 have involved many diseases, and inflammation and tumors have been studied more. At the same time, ANXA1 and related diseases have also been extended to anti-fibrosis, regulation of hepatitis C virus, and repair of muscular dystrophy membrane.

The full-length ANXA1 protein is hydrolyzed and the N-terminus is cleaved, and a peptide chain fragment Ac2-26 formed by the 26 amino acids of the N-segment. Both ANXA1 and Ac2-26 activate and bind to specific G protein-coupled receptors (GPCRs), which are called N-formyl peptide receptor 2 (FPR2 /ALX). At the same time, the peptide Ac2-26 is also able to bind to FPR1. The full-length ANXA1 can only specifically bind to FPR2 /ALX. The N-terminal peptide of ANXA1 exerts many of the effects of full-length ANXA1 but increases resistance to cleavage of inactivated protease 3 or neutrophil elastase.

In human quiescent neutrophils, ANXA1 is abundantly present in the cytoplasm and only a small fraction is present on the surface of neutrophils. After neutrophil activation, ANXA1 rapidly mobilizes to the cell surface and binds to the corresponding receptors, thereby exerting physiological functions.ANXA1 is involved in a variety of physiological processes such as cell proliferation, cell differentiation, cell signal transduction, apoptosis, and cellular immunity.

AXNA1 and Inflammation

ANXA1 is a glucocorticoid regulatory protein with potent anti-inflammatory and pre-dissipative effects. AXA1 limits the initial steps of inflammation, especially leukocyte recruitment and inflammatory mediators. It also induces neutrophil apoptosis and increases the burial of macrophages during the inflammatory phase of remission. In addition, ANXA1 can also reduce the adhesion of neutrophils to endothelial adhesion and transendothelial migration, promote the secretion of anti-inflammatory cytokine interleukin-10 by macrophages, inhibit the activation of phospholipase A2, and down-regulate the synthesis of inflammatory arachidonic acid. Girol et al. found that full-lengthANXA1 and AC2-26 can alleviate ocular inflammation caused by endotoxin in mouse ocular tissues and in vitro ARPE-19 cells. In mouse pleurisy, ANXA1 and AC2-26 control inflammation by inducing neutrophil apoptosis. Nair et al. found thatANXA1 protects against heat-induced inflammatory stress and protects cells from potential inflammatory damage during stress.

Figure 1. Schematic model ofANXA1 and Ac2-26 peptide mechanism of action in EIU. (Girol, et al. 2013)

In recent years, anti-inflammatory studies ofANXA1 have focused on the development ofANXA1-derived peptides. For example, ANXA12-50 is better able to bind to FPR2/ALXR in various animal models, resulting in better anti-inflammatory and pre-dissipative effects. When AC2-26 is combined with collagen IV and specific nanoparticles, the anti-inflammatory ability of Ac2-26 is further enhanced, and this combination is further validated in a mouse model of gluten-induced peritonitis. Furthermore, the CR-AnxA12-5 peptide is resistant to degradation by neutrophils by human protease 3, restricts the interaction of neutrophils and endothelial cells, enhances neutrophil apoptosis and macrophage phagocytosis. Under a range of inflammatory conditions, theANXA1 system represents an innovative treatment.

ANXA1 and Tumor

ANXA1 dysregulation have been reported in several oncology studies, suggesting that this protein may play an important role in tumor development and progression. Deletion of ANXA1 expression has been observed in breast cancer, gastric cancer, esophageal cancer, prostate cancer, bladder cancer, head and neck cancer, laryngeal cancer, oral cancer, and is associated with tumorigenesis and malignant propensity.ANXA1 expression was up-regulated in lung cancer, breast cancer, pancreatic cancer, cervical cancer, bladder cancer, renal cancer, and pituitary tumors. It can be seen that in breast cancer and bladder cancer, the ANXA1 expression is contradictory and cannot be explained at present. Whether it is an up-regulation or deletion of expression, ANXA1 is predicted to be a marker for the diagnosis of certain cancers in the future.

Martínezaguilar studies have shown that ANXA1 in combination with S100A6 and S100A11 can be used to distinguish between follicular and papillary carcinomas in thyroid tumors. On the other hand, many studies have confirmed a correlation between ANXA1 and tumorigenesis, invasiveness, and metastasis. ANXA1 may regulate breast cancer and increase metastatic potential through NF-κB. It has also been reported that ANXA1 promotes metastasis formation by enhancing the TGF-β/Smad signaling pathway in breast cancer.

Okano et al. cultured MDAMB-231 cells in vitro, which are triple negative breast cancer cells and highly express ANXA1. Subsequent knockdown of ANXA1 with siRNA revealed a decrease in cell invasiveness, suggesting that up-regulation of ANXA1 promotes cell invasion in Sanyin breast cancer cells. In vivo and in vitro experiments with Gastardelo et al. in laryngeal squamous cell carcinoma, ANXA1 is mediated by FPR/ALX-mediated tumor growth and metastasis via a paracrine mechanism. The results of such studies suggest that ANXA1 may be a potential therapeutic target for the treatment of malignant diseases.

However, ANXA1 gene expression levels were negatively correlated with overall survival in patients with glioblastoma multiforme, suggesting that ANXA1 can be used as a prognostic indicator for patients with this type of tumor. Similarly, relevant studies have pointed out that for the moment, ANXA1 has achieved certain results in the study of tumors, but there are still some contradictions, and more reasonable experiments are needed to deeply study the relevant mechanisms.

References:

  1. Girol, A. P., Mimura, K. K., Drewes, C. C., Bolonheis, S. M., Solito, E., & Farsky, S. H., et al. (2013). Anti-inflammatory mechanisms of the annexin a1 protein and its mimetic peptide ac2-26 in models of ocular inflammation in vivo and in vitro. Journal of Immunology, 190(11), 5689-701.
  2. Nair, S., Arora, S., Lim, J. Y., Lee, L. H., & Lim, L. H. (2015). The regulation of tnfα production after heat and endotoxin stimulation is dependent on annexin-a1 and hsp70. Cell Stress & Chaperones, 20(4), 583-593.
  3. Biaoxue, R., Xiguang, C., & Shuanying, Y. (2014). Annexin a1 in malignant tumors: current opinions and controversies. Int J Biol Markers, 29(1), 8-20.
  4. Martínezaguilar, J., Cliftonbligh, R., & Molloy, M. P. (2015). A multiplexed, targeted mass spectrometry assay of the s100 protein family uncovers the isoform-specific expression in thyroid tumours. Bmc Cancer, 15(1), 1-14.
  5. Okano, M., Kumamoto, K., Saito, M., Onozawa, H., Saito, K., & Abe, N., et al. (2015). Upregulated annexin a1 promotes cellular invasion in triple-negative breast cancer. Oncology Reports, 33(3), 1064-70.
  6. Gastardelo, T. S., Cunha, B. R., Raposo, L. S., Maniglia, J. V., Cury, P. M., & Lisoni, F. C., et al. (2014). Inflammation and cancer: role of annexin a1 and fpr2/alx in proliferation and metastasis in human laryngeal squamous cell carcinoma. Plos One, 9(12), e111317.

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