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Background and Aims <p>Liver metastasis significantly contributes to poor survival in patients with colorectal cancer (CRC), posing therapeutic challenges due to limited understanding of its mechanisms. We aimed to identify a potential target critical for CRC liver metastasis.</p> Methods <p>We analyzed the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases and identified EphrinA3 (EFNA3) as a potential clinically relevant target. The interacting proteins of EFNA3 were investigated by co-immunoprecipitation. The role of EphA3/EFNA3 axis were examined using EFNA3 knockdown and overexpressed CRC cells by transwell, wound healing, cell viability, colony formation and apoptosis assays, as well as subcutaneous and spleen injection tumour models in nude mice.</p> Results <p>EFNA3 expression was significantly higher in CRC tissues than in para-carcinoma tissues, and elevated in metastatic tissues compared to primary CRC tissues. Higher EFNA3 was significantly correlated with advanced tumour stages and unfavourable clinical outcomes in CRC patients. Functional assays suggested that EFNA3 knockdown inhibited the migration, invasion and proliferation of CRC cells both in vitro and in vivo, while EFNA3 overexpression had opposite effects. Mechanistically, EphA3 was confirmed to bind to EFNA3, and EphA3/EFNA3 reverse signalling was found to promote epithelial-to-mesenchymal transition (EMT) by activating extracellular signal-regulated kinase (ERK) 1/2 signalling, thereby promoting metastasis.</p> Conclusion <p>Our findings suggest that EFNA3 promotes CRC metastasis, and that EphA3/EFNA3 signalling may promote EMT by activating the ERK signalling. These results indicate that the EphA3/EFNA3 axis could be a potential target for metastatic CRC.</p> Graphical Abstract <p>Recombinant human EphA3 protein (rhEphA3) binds to EFNA3, and activates ERK signalling, increasing expression of Snail and inhibiting expression of E-cadherin, thereby promoting tumour progression. ERK inhibitor (AG126) inhibits rhEphA3/EFNA3 induced-EMT by inhibiting ERK phosphorylation</p>

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EphA3/EFNA3 Reverse Signalling Promotes Epithelial-to-Mesenchymal Transition via ERK Pathway to Facilitate Colorectal Cancer Metastasis

  • 期刊论文

  • 发表日期：

    2025年9月10日

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  • Ying Tan,
  • Xian Zhang,
  • Jin Wang,
  • Xue Xiao,
  • Jin-Lin Yang

摘要

Background and Aims

Liver metastasis significantly contributes to poor survival in patients with colorectal cancer (CRC), posing therapeutic challenges due to limited understanding of its mechanisms. We aimed to identify a potential target critical for CRC liver metastasis.

Methods

We analyzed the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases and identified EphrinA3 (EFNA3) as a potential clinically relevant target. The interacting proteins of EFNA3 were investigated by co-immunoprecipitation. The role of EphA3/EFNA3 axis were examined using EFNA3 knockdown and overexpressed CRC cells by transwell, wound healing, cell viability, colony formation and apoptosis assays, as well as subcutaneous and spleen injection tumour models in nude mice.

Results

EFNA3 expression was significantly higher in CRC tissues than in para-carcinoma tissues, and elevated in metastatic tissues compared to primary CRC tissues. Higher EFNA3 was significantly correlated with advanced tumour stages and unfavourable clinical outcomes in CRC patients. Functional assays suggested that EFNA3 knockdown inhibited the migration, invasion and proliferation of CRC cells both in vitro and in vivo, while EFNA3 overexpression had opposite effects. Mechanistically, EphA3 was confirmed to bind to EFNA3, and EphA3/EFNA3 reverse signalling was found to promote epithelial-to-mesenchymal transition (EMT) by activating extracellular signal-regulated kinase (ERK) 1/2 signalling, thereby promoting metastasis.

Conclusion

Our findings suggest that EFNA3 promotes CRC metastasis, and that EphA3/EFNA3 signalling may promote EMT by activating the ERK signalling. These results indicate that the EphA3/EFNA3 axis could be a potential target for metastatic CRC.

Graphical Abstract

Recombinant human EphA3 protein (rhEphA3) binds to EFNA3, and activates ERK signalling, increasing expression of Snail and inhibiting expression of E-cadherin, thereby promoting tumour progression. ERK inhibitor (AG126) inhibits rhEphA3/EFNA3 induced-EMT by inhibiting ERK phosphorylation