Attenuated LKB1-SIK1 signaling promotes epithelial-mesenchymal transition andradioresistance ofnon-small cell lung cancer cells
10.1186/s40880-016-0113-3
- Author:
YuanHuYao
1
;
YanCui
;
XiangNanQiu
;
LongZhenZhang
;
WeiZhang
;
HaoLi
;
JinMingYu
Author Information
1. Shandong University School of Medicine
- Keywords:
Radioresistance;
Lung cancer;
Metastasis;
Epithelial-mesenchymal transition;
LKB1;
SIK1
- From:Chinese Journal of Cancer
2016;35(10):500-508
- CountryChina
- Language:Chinese
-
Abstract:
Background:Radiotherapy is one of the main therapeutic approaches for non–small cell lung cancer (NSCLC).
However, radioresistant cancer cells can eventually cause tumor relapse and even fatal metastasis. It is thought that radioresistance and metastasis could be potentially linked by epithelial?mesenchymal transition (EMT). In this study, we established radioresistant NSCLC cells to investigate the potential relationship among radioresistance, EMT, and enhanced metastatic potential and the underlying mechanism involving liver kinase B1 (LKB1)?Salt?inducible kinase 1 (SIK1) signaling.
Methods:The radioresistant cell lines A549R and H1299R were generated by dose?gradient irradiation of the paren?tal A549 and H1299 cells. The radioresistance/sensitivity was evaluated by Cell Counting Kit?8 assay, apoptosis analysis, and/or clonogenic cell survival assay. The EMT phenotype and the signaling change were assessed by Western blot?ting. The abilities of invasion and migration were evaluated by transwell assays and wound healing assays.
Results:The radioresistant cell lines A549R and H1299R displayed mesenchymal features with enhanced invasion and migration. Mechanistically, A549R and H1299R cells had attenuated LKB1?SIK1 signaling, which leaded to the up?regulation of Zinc?ifnger E?box?binding homeobox factor 1 (ZEB1)—a transcription factor that drives EMT. Re?expression of LKB1 in A549R cells reversed the EMT phenotype, whereas knockdown of LKB1 in H1299R cells further promoted the EMT phenotype. Moreover, re?expression ofLKB1 in A549 cells increased the radiosensitivity, whereas knockdown ofLKB1 in H1299 cells decreased the radiosensitivity.
Conclusions:Our ifndings suggest that attenuated LKB1?SIK1 signaling promotes EMT and radioresistance of NSCLC cells, which subsequently contributes to the enhanced metastatic potential. Targeting the LKB1?SIK1?ZEB1 pathway to suppress EMT might provide therapeutic beneifts.
