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ANXA3

Official Full Name
annexin A3
Background
This gene encodes a member of the annexin family.Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways.This protein functions in the inhibition of phopholipase A2 and cleavage of inositol 1,2-cyclic phosphate to form inositol 1-phosphate. This protein may also play a role in anti-coagulation.
Synonyms
ANXA3; annexin A3; 1 2 cyclic inositol phosphate phosphodiesterase; 2-cyclic phosphate 2-phosphohydrolase; 35 alpha calcimedin; 35-alpha calcimedin; Annexin III; Annexin-3; AnnexinA3; AnnexinIII; ANX 3; ANX A3; ANX3; ANXA 3; ANXA3_HUMAN; Calcimedin 35 alpha; Inositol 1 2 cyclic phosphate 2 phosphohydrolase; Inositol 1; Lipocortin III; LipocortinIII; OTTHUMP00000160701; OTTHUMP00000219237; OTTHUMP00000219238; PAP III; PAP-III; PAPIII; Placental anticoagulant protein III; calcimedin 35-alpha; Annexin III (lipocortin III); inositol 1,2-cyclic phosphate 2-phosphohydrolase; annexin III (lipocortin III, 1,2-cyclic-inositol-phosphate phosphodiesterase, placental anticoagulant protein III, calcimedin 35-alpha)

Annexin A3 (ANXA3) is a component of the annexin superfamily. Anxa3 is expressed in differentiated cells of myeloid cell lines and increases in expression when these cells differentiate into neutrophils and macrophages, up to 1% of total cytoplasmic proteins. Anxa3 shares high structural homology with other members of annexin, especially similar to Anxa5. The four conserved "annexin in repeat" domains (I-IV) at the C-terminus are arranged in a circular form, each consisting of 5 α helices (A-E). The N-terminus contains 20 amino acid residues. The Ca2+ binding site is located on the convex surface formed by the spiral of each of the domains A and B.

ANXA3 contains two tryptophan residues (Trp, W), one at position 5 of the N-terminal sequence (W5), and one at its domain III (IIIA-IIIB ring structure) 190th residue (W190). W190 is located on the interface where ANXA3 is bonded to the membrane, while W5 is located on the opposite side of the interface between W190 and ANXA3. The W5 and W190 residues have an effect on the interaction between ANXA3 and Ca2+ and phospholipid membranes. Both of them can cause changes in Ca2+ concentration when ANXA3 needs to interact with the membrane, which in turn affects the permeability of ANXA3 to the membrane. The microenvironment near the ANXA3 domain IIIW190 and the flexible N-terminus (especially W5) affect the membrane binding and action properties of ANXA3, and their roles are interrelated. The movement of the hinge region caused by the binding of ANXA3 to the membrane causes a change in the angle between the structural modules, allowing the calcium ion pathway to open and function.

The study found that ANXA3 has two isomers, 33kDa and 36kDa molecular weight. In the brain tissue of mice, the presence of these two isomers was detected, and in the mouse cerebral ischemia model, only a small molecular weight ANXA3 protein expression was increased compared with normal brain tissue. It has been reported that the expression of two forms of ANXA3 isomers in cancer cells of renal cell carcinoma. Compared with normal renal cortical cells, the expression level of total protein of ANXA3 is down-regulated, the expression of 36kDa isomer is increased, and the isomer of 33kDa is decreased. For the relationship between the two isomers, some studies suggest that the isomer of 36 kDa in monocytes is not a post-translational modification of small molecular weight isomers, such as phosphorylated or glycosylated products. Like the isomers of other members of the annexin family, these two molecular weight isomers are thought to be involved in alternative splicing during transcription, ie, selective splicing of exon III results in a loss of 39 amino acids. Further, two kinds of proteins having different molecular weights are produced.

ANXA3 and Tumor

ANXA3 plays a role in cell differentiation, cell migration, immune regulation and bone formation. In recent years, ANXA3 has been shown to play a role in a variety of tumor developments. Studies have shown that the abnormal expression of ANXA3 is closely related to ovarian cancer, lung adenocarcinoma, prostate cancer, liver cancer, kidney cancer, colorectal cancer, pancreatic cancer, and has become a new target for cancer treatment.

Ton et al. found that endogenous and secreted annexin A3 (ANXA3) plays a key role in promoting cancer and stem cell-like features in CD133+ liver CSCs (in CD133+ liver CSCs), via the dysregulated JNK pathway. Blocking ANXA3 by anti-ANXA3 monoclonal antibodies in vitro and in human hepatoma HCC xenograft models resulted in a significant reduction in tumor growth and self-renewal. Clinically, the expression of ANXA3 in the serum of patients with hepatocellular carcinoma(HCC) is closely related to the invasive clinical features. The results show that ANXA3 can be used as a new diagnostic biomarker. Inhibition of ANXA3 may be a viable therapeutic option for the treatment of CD133+ liver-CSC-driven HCC.

Figure 1. ANXA3/JNK Signaling Promotes Self-Renewal and Tumor Growth. (Tong, et al 2015)

Bashar et al. elucidated the expression of ANXA3 in cell culture lysates and conditioned medium from tumorous breast cell lines, and its role in tumor-induced breast cell migration in vitro. The new role of ANXA3 as a breast biomarker, modulator, and therapeutic target was confirmed. Pan et al. found a significant increase in ANXA3 expression in HCC tissues compared to adjacent non-tumor tissues. The elevated ANXA3 expression is associated with tumor size, number of lesions, tumor stage, and poor prognosis. In hepatoma cell lines, exogenous ANXA3 transduction promotes the tumorigenic activity and metastatic potential of tumor cells. ANXA3's siRNA silencing inhibits these processes. In addition, in vitro and in vivo experiments have shown that ANXA3 overexpression enhances resistance to chemotherapy.

The researchers analyzed the expression of ANXA3 in renal cell carcinoma and healthy human renal cortex cells by Western blot analysis and tissue microarray. The results showed that the overall expression of ANXA3 was down-regulated. This specific expression of ANXA3 should be closely related to kidney cancer and may be important for the treatment of renal cell carcinoma. Zeng et al. showed that ANXA3 gene may be an independent factor for lymph node metastasis of breast cancer by immunohistochemical staining of tumor tissues and nearby tissues of breast cancer patients, which can be used as an index to determine whether tumors metastasize. Studies have compared the expression of ANXA3 in gallbladder tissues between patients with gallbladder cancer and healthy patients, showing that high expression of ANXA3 is highly likely to be associated with metastasis of gallbladder carcinoma, and ANXA3 may be a new target for the treatment of gallbladder cancer.

References:

  1. Zeng, C., Ke, Z., Song, Y., Yao, Y., Hu, X., & Zhang, M., et al. (2013). Annexin a3 is associated with a poor prognosis in breast cancer and participates in the modulation of apoptosis in vitro by affecting the bcl-2/bax balance. Experimental & Molecular Pathology, 95(1), 23-31.
  2. Tong, M., Fung, T. M., Luk, S., Ng, K. Y., Lee, T., & Lin, C. H., et al. (2015). Anxa3/jnk signaling promotes self-renewal and tumor growth, and its blockade provides a therapeutic target for hepatocellular carcinoma. Stem Cell Reports, 5(1), 45-59.
  3. Bashar, Z., Jackson, T. R., Larkin, S. E. T., Cutress, R. I., Coulton, G. R., & Margaret, A. K., et al. (2015). Annexin a3 is a mammary marker and a potential neoplastic breast cell therapeutic target. Oncotarget, 6(25), 21421-21427.
  4. Pan, Q. Z., Pan, K., Weng, D. S., Zhao, J. J., Zhang, X. F., & Wang, D. D., et al. (2015). Annexin a3 promotes tumorigenesis and resistance to chemotherapy in hepatocellular carcinoma. Molecular Carcinogenesis, 54(8), 598-607.
  5. Wu, N., Liu, S., Guo, C., Hou, Z., & Sun, M. Z. (2013). The role of annexin a3 playing in cancers. Clinical & Translational Oncology, 15(2), 106-110.

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