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Axin2

Official Full Name
axin 2
Background
The Axin-related protein, Axin2, presumably plays an important role in the regulation of the stability of beta-catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta-catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair. [provided by RefSeq, Jul 2008]
Synonyms
AXIN2; axin 2; AXIL; ODCRCS; axin-2; conductin; axin-like protein; axis inhibition protein 2; DKFZp781B0869; MGC126582; MGC10366; axin-related protein; axin 2 (conductin, axil); wu:fb37c08; zgc:111942; etID37069.3

The human Axin2 protein sequence is about 89% homologous to the mouse. The human Axin2 gene is located on the long arm of the chromosome (17q23-24), and its cDNA is about 2.5 kb long and consists of 10 exons. Axin2 encodes 843 amino acids (type a) or 778 amino acids (type b) of two isoforms, of which type b lacks the sixth exon and encodes 65 amino acids.

AXIN1 and AXIN2 certain domains of proteins showing a high similarity: The regulator AXIN tankyrases protein stability binding region mediates binding of RGS region APC, β-catenin- binding region and DIX region, etc. These two AXIN proteins are generally considered to be functionally identical, as Axin2 cDNA attenuates mouse damage caused by Axin1 deficiency. However, the functions of the two are not mutually replaceable. On day 9 of the embryonic stage, Axin1-deficient mice developed death, while Axin2 homozygous variant mice were reproducible with only minor skull abnormalities. The difference in the above phenotype may be due to the different expression of Axin1 and Axin2, Axin1 is ubiquitously expressed in different tissues and the expression of Axin2 is more temporally and spatially specific.

Guido and other studies have shown that the liver's microenvironment plays an important role in driving hepatic stem/progenitor cells (HpSC). The newly discovered third ecological site is around the hepatocytes, including Axin2 monoenergetic hepatocyte progenitor cells, whose lateral edges are connected to endothelial cells that are intended to be central veins, which contribute to the normal renewal of mature hepatocytes. Stem/progenitor cells are of great importance in the regenerative medicine of the liver and in the process leading to tissue diseases.

Axin2 and Wnt Pathways

Similar to Axin1, Axin2 protein also negatively regulates β-catenin-dependent Wnt signaling. Axin2 is a transcriptional target of β-catenin-dependent Wnt signaling, and Axin2 expression is elevated in tumors with abnormal activation of Wnt signaling pathway. Since the Wnt/β-catenin pathway promotes transcription of Axin2, AXIN2 can negatively regulate upstream molecules of the Wnt/β-catenin pathway. Therefore, elevated levels of Axin2 protein may be an important negative feedback mechanism for Wnt/β-catenin signaling in cells.

In normal cells, Axin2 acts as a negative regulator of the canonical Wnt signaling pathway. However, Axin2 is not a tumor suppressor gene but a potent cancer-promoting promoter that up-regulates the activity of the transcriptional inhibitor Snaill and induces EMT to stimulate metastatic activity. Studies have also found that the most important form of mutation in Axin2 is the carboxy-terminal deletion mutation (mutant Axin2, mtAxin2). mtAxin2 can cause elevated levels of β-catenin, suggesting that mtAxin2-bound β-catenin may not be phosphorylated and degraded. Wnt signaling system abnormalities are often accompanied by mitosis, apoptosis, and chromosomal instability. The Wnt signaling system is the key to cell development, and mtAxin2 plays a role in oncogenes.

Jo Waaler et al. showed that the small molecule inhibitor JW55, which uses the β-catenin signaling pathway, can inhibit the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2). This then leads to stabilization of Axin2, followed by an increase in the degradation of β-catenin.

A recent study by Chai et al. sought to determine how the Wnt/β-catenin signal is downregulated in the liver. By sequencing the small RNA isolated from the CD133+ and CD133-subpopulations of the PLC8024 HCC cell line, it was found that the expression of the microRNA miR-1246 was elevated in the CD133+ subpopulation. Since miR-1246 is predicted to target AXIN2 and GSK3β, the authors concluded that down-regulation of these genes by miR-1246 may drive HCC. After demonstrating that AXIN2 and GSK3β are directly targeted by miR-1246, they found that shRNA-mediated consumption of miR-1246 in HCC cells increased AXIN2 and GSK3β protein levels in the cytoplasm, decreased β-catenin levels in the nucleus and expression of the Wnt target gene.

Figure 1. Wnt/β-catenin activation and lower expression of Axin2 by miR-1246 in CD133+ liver CSCs, (Eshelman M A, et al. 2016)

Paul T. Sharpe et al. used TOPgal and BATgal reporter mice to study the expression of the classical Wnt signaling pathway antagonist Axin2 in tooth development. It can be seen that as the teeth develop, Axin2 precedes the primary enamel nodules and secondary enamel nodules and the mesenchyme below them. After the mouse was born, Axin2 was mainly expressed in the developing dentin, dental papilla and developing root regions, while Axin2 expression was not detected in the enamel cells and the non-enamel regions of the crown. These results indicate that the classical Wnt signaling pathway antagonist Axin2 plays an important role in enamel formation and root development in late tooth development.

Axin2 and Tumor

Researchers combined more than twenty proinflammatory mediators as a source, with thirty-one cancer genes as targets. Proinflammatory mediators are associated with cancer and the network is complex. This indicates that IL-1 and TADC act through the APC and p53 pathways, targeting the CDH1, p53 and AXIN2 genes. These genes are responsible for gastric cancer, colon cancer, breast cancer, brain cancer, and adrenal cancer. IL-8 and TAM act through the APC pathway that targets the AXIN2 gene, which is responsible for colon cancer. And studies have shown that Axin2 gene can play a role in malignant melanoma, gastric cancer and colon cancer.

Schaal et al. found that the aberrant activation of the Wnt / β-catenin pathway plays a major role in the development of colorectal cancer (CRC) and got conclusion that Axin2 is a key protein of this pathway and it is up-regulated in CRC. Aristizabalpachon et al. evaluated the AXIN2 rs2240308 and rs151279728 polymorphisms and the expression profile of β-catenin-destroying complex genes in breast cancer patients, demonstrating that AXIN2 gene defects and disruption of β-catenin disruption complex expression may be present in breast cancer patients.

Studies have shown that liver cancer stem cells (CSCs) initiate liver cancer. The research group also investigated the exact mechanism of the origin of CSCs in liver cirrhosis and liver cancer, and found that Met / JNK and Met / STAT3 signals in Axin2 + hepatocytes are activated by autophagy-dependent HGF expression, resulting in CD90 + CSCs of Axin2 + hepatocytes source, which is the main mechanism of liver cancer in liver cirrhosis. Hu et al. found that low Axin2 expression was associated with prostate cancer (PCa) recurrence after prostatectomy (RP), and its expression in PCa cells significantly affected invasiveness, proliferation, and tumor growth.

Reference:

  1. Li J, Hu S B, Wang L Y, et al. Autophagy-dependent generation of Axin2+ cancer stem-like cells promotes hepatocarcinogenesis in liver cirrhosis. Oncogene, 2017, 36(48):6725-6737.
  2. Hu B R, Fairey A S, Madhav A, et al. AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth. Prostate, 2016, 76(6):597-608.
  3. Schaal U, Grenz S, Merkel S, et al. Expression and localization of axin 2 in colorectal carcinoma and its clinical implication. International Journal of Colorectal Disease, 2013, 28(11):1469.
  4. Yang L H, Han Y, Li G, et al. Axin gene methylation status correlates with radiosensitivity of lung cancer cells. BMC Cancer. 2013, 13(1):1-12.
  5. Eshelman M A, Yochum G S. The Wnt/β-catenin pathway is activated by miR-1246 in liver cancer stem cells. Translational Cancer Research, 2016, 5(S7):S1457-S1460.

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