EphB4 Gene Editing    

EphB4 is a cell surface protein from the Ephrin tyrosine kinase receptor family. The members of the EphB subfamily are transmembrane proteins, which play a role in various processes regarding tissue architecture and cellular growth, especially in the development of nervous and vascular systems. The research on the angiogenic role of EphB4 mainly focuses on embryonic and retinal vasculogenesis. EphB4 and its ligand Ephrin B2 are involved in mammary morphogenesis in normal breast tissue. EphB4 is also reported to be abundantly present in many kinds of solid tumors, including prostate cancer, gastric cancer, colorectal cancer, and breast cancer, suggesting a common mechanism in carcinogenesis. However, the role of EphB4 in tumorigenesis is much more complex than in normal tissue, with tumor suppressing as well as tumor promoting effects.

Figure 1. Schematic domain structure of EphB4 and its ligand, ephrinB2. (Chen Y, et al. 2019)

The Function of EphB4 in Cancer

Because many tumor cells express varying degrees of Eph receptors and ligands, the functions of the Eph/ephrin system in cancer are complex. Eph-ephrin complexes transduce emanate bidirectional signals: forward signals depend on Eph kinase activity for propagation in receptor-expressing cells, while reverse signals depend on Src family kinases for propagation in the ephrin-expressing cells. Eph receptors and ephrins are widely expressed in tumor stroma and cancer cells, but may be down regulated in advanced stages of cancer. In addition, dysregulating mutations affecting Eph function also play a role in cancer pathogenesis.

EPHB4/ephrinB2 signaling promotes tumor growth, invasiveness, tumor angiogenesis and chemoresistance. In bladder cancer, EPHB4 overexpression is partly regulated by epidermal growth factor receptor (EGFR) signaling and promotes cancer survival by antiapoptosis signaling. In esophageal tumors, the EPHB4 gene appears amplified, which contributes to the survival and migration of tumor cells. Expression of EPHB4 was associated with clinically aggressive disease in gastric and gastroesophageal junction tumors. In colorectal cancer, EPHB4 was shown to not only promote tumor growth, but also promote tumor-associated angiogenesis. Studies in ovarian cancer have shown that EPHB4 expression is associated with poorer survival, and targeting EPHB4 had promising preclinical activity. Overexpression of the EPHB4 ligand ephrinB2 has also been associated with poor outcome in some tumors.

EphB4 receptors appear to be highly expressed in many cancer cell lines, but poorly activated by ephrins, as evaluated by the low level of tyrosine phosphorylation. For example, compared with nontransformed MCF10A epithelial cells, EphB4 tyrosine phosphorylation is much lower in breast cancer cell lines. This is one of the clues suggesting that ephrin-dependent Eph forward signaling might be harmful to tumor progression. In addition, forcing EphB4 receptor activation with soluble Fc fusion proteins of ephrin ligands can inhibit survival, proliferation, and migration of many types of cancer cells in culture as well as tumor growth in mouse models. EphB4 receptors that are activated by ephrins acquire the remarkable ability to inhibit oncogenic signaling pathways, including Abl-Crk, HRAS-Erk and PI3K-Akt.

EphB4 as a Therapeutic Target in Cancer

Eph receptors and ephrins are promising new targets for the treatment of cancer. Various strategies were used to evaluate the interference of tumor-promoting effects or the enhancement of tumor suppressive effects. The inhibition of the Eph-ephrin system may be particularly useful for anti-angiogenic therapies. EphB4 inhibitors have been studied over the past several years, with many different methods used to test for inhibition of activity or competitive binding affinity as a novel therapeutic modality to treat malignancy. Several effective Eph kinase inhibitors were reported either based on high molecular weight compounds like peptides, which blocking the extracellular domain of the appropriate receptor, or on small organic molecules, which bind to the intramolecular ATP- binding pocket and inhibit EphB4 kinase activity.

EPHB4 Gene Editing Services

CRISPR/Cas9 Platform^CB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively EPHB4 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

• EPHB4 Gene Knockout: We offer EPHB4 gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service covers from sgRNA design and construction, pronuclear microinjection to Founders genotyping and breeding.
• EPHB4 Gene Knockin: CRISPR/Cas9 Platform^CB provides the one-stop EPHB4 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of EPHB4 knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

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