EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancer
Objective: Non-small lung cancer (NSCLC) is the most prevalent form of lung cancer, and it is often associated with poor patient outcomes. Erythropoietin-producing hepatocellular receptor A5 (EPHA5), a member of the Eph tyrosine kinase receptor family, has been implicated in various stages of tumor...
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Elsevier
2025-03-01
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| Series: | Advances in Cancer Biology - Metastasis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667394025000048 |
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| author | Jie Li Yehan Zhu |
| author_facet | Jie Li Yehan Zhu |
| author_sort | Jie Li |
| collection | DOAJ |
| description | Objective: Non-small lung cancer (NSCLC) is the most prevalent form of lung cancer, and it is often associated with poor patient outcomes. Erythropoietin-producing hepatocellular receptor A5 (EPHA5), a member of the Eph tyrosine kinase receptor family, has been implicated in various stages of tumor progression. However, the specific role of EPHA5 in NSCLC remains poorly understood. This study aims to explore the influence of EPHA5 on the stemness of NSCLC cancer cells and their sensitivity to gefitinib, while also investigating the underlying mechanisms involved. Methods: EPHA5 expression was suppressed using small interfering ribonucleic acids (siRNAs), while qPCR and Western blot were applied to analyze the knockdown efficiency. Subsequently, the expressions of stem cell-related markers, such as SOX2, Nanog, KLF4, Oct4, and β-catenin, were detected and quantified via qPCR and Western blot during the experiment, while CD133-positive cells were analyzed via flow cytometry. Gefitinib sensitivity was evaluated in EPHA5-knockdown cells. The Wnt activator, CHIR-99021, was employed to rescue β-catenin expression. Results: EPHA5 expression was elevated in NSCLC cell lines (NCI-H460 and NCI-H1229) but considerably downregulated by siRNAs. EPHA5 knockdown alleviated stemness, enhanced gefitinib sensitivity, and suppressed Wnt activation, as evidenced by lower CD133-positive cells, and decreased expression of Sox2, Nanog, KLF4, Oct4, and β-catenin. The Wnt activator reversed the inhibitory effect of EPHA5 on cancer cell stemness by upregulating β-catenin. Conclusion: Silencing the expression of EPHA5 can reduce NSCLC stemness and enhance gefitinib sensitivity by inhibiting the Wnt signaling pathway. Strengths and limitations of this study: We find EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway of non-small cell lung cancer but prognostic follow-up of lung adenocarcinoma patients in this study is lacking. |
| format | Article |
| id | doaj-art-cca116d6d7e94f4e9734d9d20f54d962 |
| institution | DOAJ |
| issn | 2667-3940 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Advances in Cancer Biology - Metastasis |
| spelling | doaj-art-cca116d6d7e94f4e9734d9d20f54d9622025-08-20T02:57:33ZengElsevierAdvances in Cancer Biology - Metastasis2667-39402025-03-011310013510.1016/j.adcanc.2025.100135EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancerJie Li0Yehan Zhu1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Department of Respiratory and Critical Care Medicine, Jiangyin School of Clinical Medicine, Jiangsu University, Jiangyin, 214400, ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Corresponding author.Objective: Non-small lung cancer (NSCLC) is the most prevalent form of lung cancer, and it is often associated with poor patient outcomes. Erythropoietin-producing hepatocellular receptor A5 (EPHA5), a member of the Eph tyrosine kinase receptor family, has been implicated in various stages of tumor progression. However, the specific role of EPHA5 in NSCLC remains poorly understood. This study aims to explore the influence of EPHA5 on the stemness of NSCLC cancer cells and their sensitivity to gefitinib, while also investigating the underlying mechanisms involved. Methods: EPHA5 expression was suppressed using small interfering ribonucleic acids (siRNAs), while qPCR and Western blot were applied to analyze the knockdown efficiency. Subsequently, the expressions of stem cell-related markers, such as SOX2, Nanog, KLF4, Oct4, and β-catenin, were detected and quantified via qPCR and Western blot during the experiment, while CD133-positive cells were analyzed via flow cytometry. Gefitinib sensitivity was evaluated in EPHA5-knockdown cells. The Wnt activator, CHIR-99021, was employed to rescue β-catenin expression. Results: EPHA5 expression was elevated in NSCLC cell lines (NCI-H460 and NCI-H1229) but considerably downregulated by siRNAs. EPHA5 knockdown alleviated stemness, enhanced gefitinib sensitivity, and suppressed Wnt activation, as evidenced by lower CD133-positive cells, and decreased expression of Sox2, Nanog, KLF4, Oct4, and β-catenin. The Wnt activator reversed the inhibitory effect of EPHA5 on cancer cell stemness by upregulating β-catenin. Conclusion: Silencing the expression of EPHA5 can reduce NSCLC stemness and enhance gefitinib sensitivity by inhibiting the Wnt signaling pathway. Strengths and limitations of this study: We find EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway of non-small cell lung cancer but prognostic follow-up of lung adenocarcinoma patients in this study is lacking.http://www.sciencedirect.com/science/article/pii/S2667394025000048EPHA5Non-small lung cancerWnt signaling pathwayStemnessMolecular mechanism |
| spellingShingle | Jie Li Yehan Zhu EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancer Advances in Cancer Biology - Metastasis EPHA5 Non-small lung cancer Wnt signaling pathway Stemness Molecular mechanism |
| title | EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancer |
| title_full | EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancer |
| title_fullStr | EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancer |
| title_full_unstemmed | EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancer |
| title_short | EPHA5 enhances stemness and decreases gefitinib sensitivity via Wnt signaling pathway in non-small lung cancer |
| title_sort | epha5 enhances stemness and decreases gefitinib sensitivity via wnt signaling pathway in non small lung cancer |
| topic | EPHA5 Non-small lung cancer Wnt signaling pathway Stemness Molecular mechanism |
| url | http://www.sciencedirect.com/science/article/pii/S2667394025000048 |
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