Epha5, a member of the Eph family of tyrosine kinase receptors, plays a role in various biological processes and is associated with multiple signaling pathways such as the Wnt/β -catenin pathway. It has been implicated in carcinogenesis and is important for understanding tumor-related biological functions [3,7,8].

In lung adenocarcinoma, EPHA5 mutations are correlated with enhanced infiltration of CD8+ T cells and M1 macrophages, reduced recruitment of immunosuppressive regulatory T cells, increased levels of chemokine, interferon-gamma, inhibitory immune checkpoint signatures, tumor mutation burden, and tumor neoantigen burden. EPHA5-mutant patients treated with immunotherapy have prolonged survival times [1]. In esophageal squamous cell carcinoma, EphA5 silencing increases radiosensitivity through the ATM-dependent pathway [2]. In non-small cell lung cancer, EPHA5 mutation promotes cell migration and invasion and impairs natural killer cell-mediated cytotoxicity [5]. In HER2-positive breast cancers, deletion of EPHA5 increases trastuzumab resistance by enhancing cancer stem cell-like properties [4]. In gastric cancer, abnormal EPHA5 methylation in peripheral blood leukocytes is related to the cancer risk [6]. In non-small cell lung cancer cells, EPHA5 enhances stemness through activating the Wnt signaling pathway [7]. In esophageal squamous cell carcinoma, EphA5 knockdown promotes proliferation, invasion, and migration via epithelial-mesenchymal transition through activating the Wnt/β-catenin pathway [8].

In conclusion, Epha5 is a key gene involved in cancer-related biological functions. Research on Epha5, especially through gene-knockout or other loss-of-function models, has provided valuable insights into its role in tumor immunity, radiosensitivity, drug resistance, and cell stemness in various cancers, such as lung, esophageal, breast, and gastric cancers. These findings may contribute to the development of new prognostic markers and treatment strategies for these diseases.

References:

1. Chen, Zhiming, Chen, Ji, Ren, Dandan, Mao, Beibei, Ma, Haitao. 2020. EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma. In Aging, 13, 598-618. doi:10.18632/aging.202169. https://pubmed.ncbi.nlm.nih.gov/33288738/

2. Zhang, Rui, Han, Dan, Li, Lu, Liu, Jing, Qian, Liting. 2020. EphA5 Silencing Increases the Radiosensitivity of ESCC Cells Through ATM-Dependent Pathway. In Cancer management and research, 12, 9539-9549. doi:10.2147/CMAR.S261182. https://pubmed.ncbi.nlm.nih.gov/33061640/

3. Liu, Chengying, He, Yan, Feng, Xiao, Li, Jie, Wang, Jiandong. 2022. Expression of EPHA5 in lung adenocarcinoma is associated with lymph node metastasis and EGFR mutation. In APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 130, 338-345. doi:10.1111/apm.13222. https://pubmed.ncbi.nlm.nih.gov/35332588/

4. Li, Yongfei, Chu, Jiahui, Feng, Wanting, Huang, Yi, Yin, Yongmei. 2019. EPHA5 mediates trastuzumab resistance in HER2-positive breast cancers through regulating cancer stem cell-like properties. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 4851-4865. doi:10.1096/fj.201701561RRRR. https://pubmed.ncbi.nlm.nih.gov/30620624/

5. Zhang, Jingwen, Zhang, Zhihao, Song, Weiwei, Liu, Jumin. 2020. EPHA5 mutation impairs natural killer cell-mediated cytotoxicity against non-small lung cancer cells and promotes cancer cell migration and invasion. In Molecular and cellular probes, 52, 101566. doi:10.1016/j.mcp.2020.101566. https://pubmed.ncbi.nlm.nih.gov/32234341/

6. Han, Xu, Liu, Tianyu, Zhai, Jiabao, Zhou, Haibo, Tian, Wenjing. 2022. Association between EPHA5 methylation status in peripheral blood leukocytes and the risk and prognosis of gastric cancer. In PeerJ, 10, e13774. doi:10.7717/peerj.13774. https://pubmed.ncbi.nlm.nih.gov/36164608/

7. Li, Jie, Zhu, Yehan. . EPHA5 Enhances the Stemness of Non-small cell lung cancer Cells Through Activating the Wnt Signaling Pathway. In Journal of B.U.ON. : official journal of the Balkan Union of Oncology, 26, 1871-1878. doi:. https://pubmed.ncbi.nlm.nih.gov/34761594/

8. Zhang, Rui, Liu, Jing, Zhang, Wei, Qian, Li-Ting, Zhou, Shao-Bing. 2020. EphA5 knockdown enhances the invasion and migration ability of esophageal squamous cell carcinoma via epithelial-mesenchymal transition through activating Wnt/β-catenin pathway. In Cancer cell international, 20, 20. doi:10.1186/s12935-020-1101-x. https://pubmed.ncbi.nlm.nih.gov/31956298/