Y-box binding protein 1 (YB-1) promotes gefitinib resistance in lung adenocarcinoma cells by activating AKT signaling an
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ORIGINAL PAPER
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) Lei Lou 1,2 & Juan Wang 1 & Fengzhu Lv 2 & Guohui Wang 3 & Yuehong Li 1 & Lingxiao Xing 2 & Haitao Shen 2 & Xianghong Zhang 1,2 Accepted: 21 August 2020 # International Society for Cellular Oncology 2020
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 YB1 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. Keywords Lung adenocarcinoma . Gefitinib resistance . Y-box binding protein 1 (YB-1) . Major vault protein (MVP)
Lei Lou and Juan Wang contributed equally to this work. * Xianghong Zhang [email protected] Lei Lou [email protected] 1
Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 050000, People’s Republic of China
2
Laboratory of Pathology, Hebei Medical University, ShijiazhuangHebei Province Shijiazhuang, Hebei 050017, People’s Republic of China
3
Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 050000, People’s Republic of China
1 Introduction Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents 80%
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