EFNA4 (Ephrin A4)

In conclusion, our results highlight that a subset of EPHs and EFNs may be associated with worse clinical outcomes (EPHA4, EPHA5, EPHA7, EPHA8, EPHB2, EFNA2, and EFNB2), and an aggressive histological subtype (EPHA2, EPHA4, EPHA8, EPHB4, EFNA1, EFNA3, EFNA4, and EFNB2). The potential correlation of these genes with clinicopathological parameters of UVM need to be evaluated and validated with bioinformatic and experimental approaches in well-characterized cohorts of UVM patients.

An integrated EFNA4-ETS1 prognostic model improves GC risk stratification. Although EFNA4 has been shown to promote metastasis in liver cancer, the contradictory mechanism of its high expression and good prognosis in GC remains to be elucidated, which may involve its antagonistic effects with ETS1, and requires further exploration.

Finally, EFNA4 expression in GC was significantly higher than that in normal tissues, and patients with GC and high EFNA4 expression exhibited improved prognosis. In conclusion, the prognosis model based on CRGs could be used as the basis for predicting the potential prognosis of patients with GC and provide new insights for the treatment of GC.

In conclusion, we demonstrated that EFNA4 promotes the proliferation and metastasis of HCC independent of Eph receptors by inhibiting ferroptosis and advancing the deubiquitination of SLC7A11 by recruiting the deubiquitinase USP9X. This indicates that EFNA4 could act as a potential prognostic marker and a prospective therapeutic target in patients with HCC.

Knockout of EFNA4 gene could significantly inhibit the proliferation and invasion of pancreatic cancer cells. Therefore, EFNA4 may be one of the molecular targets for poor prognosis of patients with pancreatic cancer.

Further elevation of Pygo2 reversed the impacts of EFNA4 silencing on Wnt/β-catenin signaling, cell proliferation, apoptosis, migration, invasion, angiogenesis as well as stemness in gastric cancer. Accordingly, the knockdown of EFNA4 might downregulate Pygo2 and inactivate Wnt/β-catenin signaling to exert protective effects against gastric cancer.

Consistently, in vivo, hyperthermia augmented the therapeutic efficacy of GEM on xenograft tumors through modulation of the ephrin A4/β-catenin/dCK axis. This study delineates the role of hyperthermia in enhancing GEM sensitivity of PC cells, primarily mediated through the suppression of the EFNA4/β-catenin axis and activation of dCK.

EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors.

Colony formation assay indicated that the overexpression of EFNA4 promoted tumor cell proliferation. These results demonstrated that EFNA4 played as an oncogenic gene and a prognostic biomarker for HCC patients.

A reduction in the expression of these genes was seen in patients who achieved pathological complete response and/or major pathological response (N=27) (EFNA1: log2FC -0.92, p=0.01; EFNA3: log2FC -1.53, p=0.0005; EFNA4: log2FC -0.75, p=0.01; EPHA1: log2FC -1.77, p<0.00001) but not amongst patients who relapsed following cystectomy (N=17). Patients with high expression levels of EFNA1 (p = 0.03) and EFNA4 (p = 0.03) post-atezolizumab had a shorter relapse-free survival than those with low expression levels.ConclusionThese findings suggest that EFNA-EPHA signalling is associated with treatment resistance to PD-L1 inhibitor therapy in muscle-invasive urothelial carcinoma, therefore representing a potential biomarker and treatment target.

The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC.

Furthermore, EFNA4 knockdown blocked wnt/β-catenin signaling in Huh7 cells, which was then abolished by PYGO2. In conclusion, this study further ensured the oncogenic role of EFNA4 in HCC, and disclosed that EFNA4 knockdown suppressed cell proliferation, invasion, angiogenesis, and wnt/β-catenin signaling in HCC by downregulating PYGO2.