Abstract
Purpose
Gefitinib is a first-line treatment option for epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. However, most patients inevitably develop gefitinib resistance. The mechanism underlying this resistance is not fully understood. Y-box binding protein 1 (YB-1) has been reported to play a role in modulating drug sensitivity, but its role in gefitinib resistance is currently unknown. Here, we investigated the role of YB-1 in gefitinib resistance of lung adenocarcinoma.
Methods
We determined the expression of YB-1, epithelial–mesenchymal transition (EMT) and AKT signaling markers, as well as the viability of lung adenocarcinoma cell lines bearing mutant (HCC827, PC-9) or wild-type (H1299) EGFR. We also evaluated PC-9 cell migration and invasion using transwell assays. The clinical importance of YB-1 and major vault protein (MVP) was evaluated using primary lung adenocarcinoma patient samples.
Results
We found that YB-1 was significantly upregulated in gefitinib-resistant lung adenocarcinoma cells compared to gefitinib-sensitive cells. YB-1 augmented gefitinib resistance by activating the AKT pathway and promoting EMT. Decreased migration and invasion was observed upon MVP silencing in YB-1-overexpressing PC-9 cells, as well as restored gefitinib sensitivity. A retrospective analysis of 85 patients with lung adenocarcinoma revealed that YB-1 levels were significantly increased in tyrosine kinase inhibitor (TKI)-resistant patients compared to those in TKI-sensitive patients, indicating that YB-1 may serve as a biomarker to clinically predict acquired gefitinib resistance.
Conclusion
YB-1 activates AKT signaling and promotes EMT at least in part by directly activating MVP. Hence, targeting the YB-1/MVP axis may help to overcome gefitinib resistance in lung adenocarcinoma patients.
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This project was supported by the National Natural Science Foundation of China (Grant No.81502634).
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LL was responsible for the study concept and design. FZ, GW and HS acquired the data for the study. JW and YL were responsible for data analysis and interpretation. LL prepared the manuscript and LX reviewed the manuscript. XZ is corresponding author. All other authors read and approved the final version of the manuscript.
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This study was approved by the Ethics Committee of The Second Hospital of Hebei Medical University, Shijiazhuang, China.
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Lou, L., Wang, J., Lv, F. et al. Y-box binding protein 1 (YB-1) promotes gefitinib resistance in lung adenocarcinoma cells by activating AKT signaling and epithelial–mesenchymal transition through targeting major vault protein (MVP). Cell Oncol. 44, 109–133 (2021). https://doi.org/10.1007/s13402-020-00556-y
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DOI: https://doi.org/10.1007/s13402-020-00556-y