EDIL3

Official Full Name

EGF like repeats and discoidin domains 3

Organism

Homo sapiens

GeneID

10085

Background

The protein encoded by this gene is an integrin ligand. It plays an important role in mediating angiogenesis and may be important in vessel wall remodeling and development. It also influences endothelial cell behavior. [provided by RefSeq, Jul 2008]

Synonyms

DEL1;

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Detailed Information

EDIL3(EGF-like repeats and discoidin I-like domains 3) is a glycoprotein with a molecular weight of 52 kDa that is secreted by endothelial cells and is present on the surface of endothelial cells and in the extracellular matrix, but not in the blood. The nitrogen terminus of EDIL3 contains a signal sequence and three epidermal growth factor repeats. Its carbon end contains two disc-like domains, which are primarily responsible for attachment to the sulfated polysaccharide and to the phosphatidylserine on the cell membrane. The second epithelial growth factor repeat contains an arginine-glycine-aspartate peptide that binds EDIL3 to integrin αvβ3 and regulates endothelial cell adhesion to EDIL.

The expression of EDIL3 was first discovered in embryonic cells containing endothelial cells and thymus, and subsequent studies have been found in adult endothelial cells, some macrophages, and hypertrophic chondrocytes. However, recently, in adult animal experiments, it has been found that EDIL3 is very abundantly expressed in lung tissues, brain tissues, and eyes, and is less abundant in the kidney. However, it is not expressed in intestinal tissues, liver tissues, heart, spleen, and whole blood circulation and bone marrow cells. Studies have shown that the main role of the EDIL3 molecule is to promote angiogenesis and is a member of the vascular endothelial growth factor superfamily. This angiogenic effect of the EDIL3 molecule is known in some studies as a switch to angiogenesis, which may make it a good therapeutic tool in some ischemic diseases. For example, in ischemic cardiomyopathy and limb ischemic diseases, this factor can promote blood vessel formation and increase local blood flow.

EDIL3 and Tumor

In the study of pancreatic cancer, Damhofer et al. found that EDIL3 is closely related to the poor prognosis of pancreatic cancer. In the pancreatic ductal cell adenocarcinoma, the survival curves of the low EDIL3 group and the high EDIL3 group were significantly different (level correlation P=0.005). High expression of the EDIL3 gene in human pancreatic ductal cell carcinoma was found by immunohistochemistry. EDIL3 blocks apoptosis and promotes endothelial cell adhesion by interacting with the integrin receptor αv/β3. In addition, overexpression of EDIL3 has also been found to accelerate the metastasis of cancer cells in cancer cell metastasis models of osteosarcoma and lung cancer. This reflects its great potential to promote tumor development by affecting tumor angiogenesis. Feng et al. found that the EDIL3 gene is enriched in cancer cells compared to normal cells by gene enrichment analysis. This protein has also been found to be overexpressed in hepatocellular carcinoma, and this overexpression also leads to poor prognosis in patients with hepatocellular carcinoma.

In the study of EDIL3 and liver cancer, Xia et al. found that EDIL3 can regulate the transformation of epithelial cells into mesenchymal cells, and this transformation is called epithelial-mesenchymal transition (EMT). EDIL3 positively regulates EMT and promotes metastasis, invasion, and angiogenesis of hepatocellular carcinoma. Related studies showed that the expression of EDIL3 was significantly positively correlated with the mesenchymal marker vimentin and negatively correlated with the epithelial marker cadherin. The mechanism by which EDIL3 positively regulates EMT is mainly: down-regulation of miR-137 expression in hepatocellular carcinoma patients regulates overexpression of EDL3 molecules, thereby interacting with αν/β3 integrin proteins and then eliciting extracellular signal-regulated kinases (ERK) and transforming growth factor-β (TGF-β) signaling pathway. The investigators concluded that blocking ERK and TGF-β signaling pathways is resistant to tumor angiogenesis and invasion and metastasis of tumors to surrounding tissues by EDIL3. By using a liver cancer model of orthotopically transplanted mice, it was found that EDIL3 can promote tumor formation, metastasis, and angiogenesis.

EDIL3 Figure 1. The possible regulatory roles of the overexpression of EDIL3, which contribute to the EMT, metastasis, recurrence and angiogenesis in HCC. (Xia, et al. 2015)

EDIL3 and Inflammation

Hajishengallis et al. found that EDIL3 restricted the aggregation of neutrophils by counteracting the interaction of the integrin molecule LFA-1 on the surface of neutrophils with the adhesion molecule ICAM-1 on the surface of endothelial cells. Studies have shown that age-related genes or EDIL3 deficient mice exhibited increased neutrophil infiltration, resulting in dentin inflammatory osteoporosis. This suggests that EDIL3 can inhibit neutrophil aggregation and infiltration. Further mechanism studies have found that this effect of EDIL3 does not affect the expression of epithelial cell-associated factors and adhesion molecules, but inhibits the release of chemokines that are dependent on intercellular adhesion molecules secreted by neutrophils. Therefore, EDIL3 may inhibit the cascade of inflammation by inhibiting chemokine-mediated aggregation of inflammatory cells. At the same time, Shin et al. also showed that the expression of EDIL3 itself is also regulated by inflammatory stimulating factors, which play the opposite role in the expression of adhesion molecules.

It is now believed that mainly EDIL3 inhibits chemokines such as CXCL2 and CCL3. IL-17 is a pro-inflammatory factor produced primarily by Th17 cells that can participate in airway inflammation. It can promote the accumulation of eosinophils and neutrophils in the airway, trigger airway allergic inflammation, and can induce the production of chemokines and Th2-related cytokines, and recruit concentrated granulocyte infiltration. Eskan et al. found that EDIL3 can locally inhibit neutrophil exudation and inhibit the inflammatory effect of IL-17.

References:

Damhofer, H., Medema, J. P., Veenstra, V. L., Badea, L., Popescu, I., & Roelink, H., et al. (2013). Assessment of the stromal contribution to sonic hedgehog‐dependent pancreatic adenocarcinoma. Molecular Oncology, 7(6), 1031-1042.
Feng, M. X., Ma, M. Z., Fu, Y., Li, J., Wang, T., & Xue, F., et al. (2014). Elevated autocrine edil3 protects hepatocellular carcinoma from anoikis through rgd-mediated integrin activation. Molecular Cancer, 13(1), 226.
Xia, H., Chen, J., Shi, M., Gao, H., Sekar, K., & Seshachalam, V. P., et al. (2015). Edil3 is a novel regulator of epithelial-mesenchymal transition controlling early recurrence of hepatocellular carcinoma. Journal of Hepatology, 63(4), 863-873.
Hajishengallis, G., & Chavakis, T. (2013). Endogenous modulators of inflammatory cell recruitment. Trends in Immunology, 34(1), 1-6.
Shin, J., Hosur, K. B., Pyaram, K., Jotwani, R., Liang, S., & Chavakis, T., et al. (2013). Expression and function of the homeostatic molecule del-1 in endothelial cells and the periodontal tissue. Clinical & Developmental Immunology, 2013(1), 617809.
Eskan, M. A., Jotwani, R., Abe, T., Chmelar, J., Lim, J. H., & Liang, S., et al. (2012). The leukocyte integrin antagonist del-1 inhibits il-17–mediated inflammatory bone loss. Nature Immunology, 13(5), 465-473.

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