Differential Expression Patterns of Eph Receptors and Ephrin Ligands in Human Cancers

Table 4

Altered expression of Eph receptors and ephrin ligands in medulloblastoma.

Eph receptor/ephrin ligand	Preferred molecular interaction	↑/↓ relative to normal tissue	Mechanism	Reference
EphA2	Ephrin-A1	↑	EphA2 overexpressed in medulloblastoma samples with vasculogenic mimicry via PI3K; PI3K signaling activates MMP-14.; MMP-14 leads to activation of pro-MMP-2 to activate MMP-2 proteinase.; Active MMP-2 cleave laming into promigratory γ2′ and γ2x fragments which ultimately lead to vascular mimicry formation	[77]
EphB1		↑	(i) Knockdown of EphB1 in DAOY and UW228 human MB cell lines result in ↓ cell proliferation and increased radiosensitization; (1) Silenced EphB2 results in decrease cyclin E → decrease phosphorylation of Rb and E21F1 → impaired Chk2 activation → G1 cell cycle arrest; (2) Cell cycle arrest results in ↓ levels of proliferating cell nuclear antigen, phosphorylated Akt and total AKT; (3) G1 phase is sensitive to radiation; (ii) EphB2 and EGFR cross-talk	[78]
EphB2		↑	(i) Overexpression EphB2 in primary medulloblastoma tissue and medulloblastoma cell lines; (ii) RNA silenced EphB2 MB cell lines unable to generate invasiveness when stimulated with ephrin-B2; (iii) Knockdown of EphB2 ↑ phosphorylation levels of Erk1/2, MSK1/2, PLCγ-1, State1/4/5a, RSK1/2, and cell mobility regulators p27 and paxillin; (iv) Ligand-dependent ephrin-B1 enhanced EphB2 expression through downstream activation of p38 and Erk signaling as well as inhibiting mTOR; (1) Ephrin-B1 may cross-talk with a serine/threonine phosphatase to dephosphorylate Akt-mTOR; (v) Knockdown of EphB2 led to accumulation of medulloblastoma cell arrest in G2/M phase in vitro; (1) G2/M phase is most sensitive to radiation therapy	[79, 80]
Ephrin-A5	EphA4; EphA7; EphB1; EphB2	↑	(i) Ephrin-A5 expression associate with medulloblastoma tumor size; (1) ND20SmoA1 ephrin-A5 knockout mice had smaller tumor sizes compared to NDS0SmoA1 ephrin-A5 mice; (2) Smo constitutive activation suppresses Ephrin-A5 in dorsal midbrain and hindbrain of E12–E15 mice and chicken embryo; (3) Ephrin-A5 overexpress in external granule cell layer (medulloblastoma precursor cells); (ii) ND20SmoA1 ephrin-A5 knockout ↓ expression of PCNA and p-Akt; (1) PI3K recruits Akt to plasma membrane; (2) 3-Phosphoinosito-dependent kinases phosphorylate AKt; (iii) PI3K/Akt promotes medulloblastoma growth in a PTEN loss dependent manner	[81–84]
Ephrin-B1	EphB2	↑	(i) Dysregulation of ephrin-B1 promotes oncogenic signaling in medulloblastoma; (1) Knockdown of ephrin-B1 in DOAY and D556 cell lines resulted in moderate decrease in phosphorylated EphB receptors compared to knockdown ephrin-B2 indicating possible reverse signaling pathway; (ii) Ephrin-B1 knockdown did not reduce phosphorylation of Src suggesting ephrin-B1 may also act outside of the eph/ephrin ax	[85]
Ephrin-B2	EphB2	↑	(i) Knockout of ephrin-B2 in DOAY and D556 cells had lesser decrease of phosphorylated EphB receptors compared to DOAY and D556 Ephrin-B1 knockout lines; (ii) DOAY and D556 cells with ephrin-B2 knockout also demonstrated reduction in phosphorylated Src	[85]