Review Article

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

Table 1

Altered expression of Eph receptors and ephrin ligands in lung cancer.

Eph receptor/ephrin ligandPreferred molecular interaction↑/↓ 
relative to normal tissue
MechanismReferences

EphA1↑ 
(NSCLC)
(i) Higher levels of EphA1, Eph4, EphA5, and EphA7 only present in nonadvance stages of lung cancer (E-COG performance score < 2)[22]

EphA2Ephrin-A1↑ 
(NSCLC)
(i) Tobacco smoke → upregulates EphA2 and downregulation of E-cadherin 
   (1) Increased protein permeability via Erk1/Erk2, p54, and JNK-MAPK 
(ii) Highest EphA2 in patients who developed brain metastasis 
(iii) Constitutive activation via phosphorylation of pSer2448 and pSer2481 in MTOR 
(iv) Loss of EphA2→ loss of EGFR mutations in vitro in TKI resistant lung cancer cells 
(v) Phrenological inhibition of EphA2 via AWL-II-41-247 resulted in decreased proliferation of TKI resistant lung cancer cells 
(vi) Ephrin-B3 silencing→ stabilization of EphA2 via phosphorylation of Akt target Ser-897
[2328]

EphA3Ephrin-B2↓ 
(SCLC)
(i) Upregulation of EphA3 → reduced PI3k/BMX/STAT3 signaling in SCLC cells → inducing G0/G1 arrest and increased apoptosis 
(ii) Ephrin-A3 coexpression inhibits EphA3 trans activation 
   (1) Ephrin-A3 is 26x upregulated in NSCLC & absent in normal lung tissue
[29, 30]

EphA4↑ 
(NSCLC)
(i) EphA4 expression correlate with low stage and presence of inflammation 
(ii) Higher levels of EphA1, Eph4, EphA5, and EphA7 only present in nonadvance stages of lung cancer (E-COG performance score < 2)
[22]

EphA5↑ 
(NSCLC)
Higher levels of EphA1, Eph4, EphA5, and EphA7 only present in nonadvance stages of lung cancer (E-COG performance score < 2)[22]

EphA7↑ 
(NSCLC)
(i) EphA7 expression correlate with older age, fibrosis, and smaller tumor size 
(ii) Higher levels of EphA1, Eph4, EphA5, and EphA7 only present in nonadvance stages of lung cancer (E-COG performance score < 2)
[22]

EphB3Ephrin-B1 
Ephrin-B2
↑ 
(NSCLC)
(i) Overexpression of EphB3→ accelerated cell growth and migration 
(ii) EphB3/Ephrin-B1→ decreased Akt activity via ternery formation of PP2A/RACK1/Akt 
(iii) EphB3 loss in vivo→ apoptosis due to increased activation of capase-8
[31, 32]

EphB4↑ & ↓ 
(paradoxical)
(i) 3x overexpression in lung cancer 
(ii) Positive correlation of EphB4 expression and lung cancer survival
[33]

Ephrin-A3(i) Ephrin-A3 mRNA expression upregulated 26-fold in squamous cell lung carcinoma 
(ii) Expression of ephrin-A3 inhibits EphA2 and EphA3 ligand-dependent activation 
(iii) EpA5 G518L lung cancer mutation enhances cis-interaction with ephrin-A3
[29, 30]

Ephrin-B2(i) Expression of ephrin-B2 in A549 lung cancer cell attenuates EphB4 as well as EphA3 ligand-dependent activation[30]

Ephrin-B3(i) Silencing of ephrin-B3 in NSCLC line and stabilization of EphA2 via Akt target Ser-897 phosphorylation may promote stability of EphA2 in tumor survival[23, 28]