1. Academic Validation
  2. 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)

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 (Dordr). 2021 Feb;44(1):109-133. doi: 10.1007/s13402-020-00556-y.
Lei Lou  # 1 2 Juan Wang  # 1 Fengzhu Lv 2 Guohui Wang 3 Yuehong Li 1 Lingxiao Xing 2 Haitao Shen 2 Xianghong Zhang 4 5
Affiliations

Affiliations

  • 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, Shijiazhuang, Hebei 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.
  • 4 Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, People's Republic of China. zhangxianghong2008@163.com.
  • 5 Laboratory of Pathology, Hebei Medical University, Shijiazhuang, Hebei Province Shijiazhuang, Hebei, 050017, People's Republic of China. zhangxianghong2008@163.com.
  • # Contributed equally.
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.

Keywords

Gefitinib resistance; Lung adenocarcinoma; Major vault protein (MVP); Y-box binding protein 1 (YB-1).

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