Background: MiR-214 has been reported to contribute to erlotinib resistance in non-small-cell lung cancer (NSCLC) through targeting LHX6; however, the molecular mechanisms underlying the involvement of LHX6 in mediating the resistance to EGFR-TKIs in erlotinib-resistant NSCLC HCC827 (HCC827/ER) cells remain unknown. This study aimed to investigate the mechanisms responsible for the contribution of LHX6 to EGFR-TKIs resistance in HCC827/ER cells. Materials and Methods: HCC827/ER cells were generated by erlotinib treatment at a dose-escalation scheme. LHX6 knockout or overexpression was modeled in HCC827 and HCC827/ER cells, and then erlotinib IC50 values were measured. The cell migration ability was evaluated using a transwell migration assay, and the TCF/LEF luciferase activity was assessed with a TCF/LEF reporter luciferase assay. LHX6, β-catenin and Cyclin D1 expression was quantified using qPCR and Western blotting assays. In addition, the LHX6 expression was detected in lung cancer and peri-cancer specimens using immunohistochemical staining, and the associations of LHX expression with the clinicopathological characteristics of lung cancer were evaluated. Results: Lower LHX6 expression was detected in HCC827/ER cells than in HCC827 cells (P < 0.0001), while higher β-catenin expression was seen in HCC827/ER cells than in HCC827 cells (P < 0.001). LHX6 knockout increased erlotinib resistance and cell migration ability in HCC827 cells, and LHX6 overexpression inhibited erlotinib resistance and cell migration ability in HCC827/ER cells. In addition, LHX6 mediated erlotinib resistance and cell migration ability in HCC827/ER cells via the Wnt/β-catenin pathway. Immunohistochemical staining showed lower LHX6 expression in lung cancer specimens relative to peri-cancer specimens, and there were no associations of LHX6 expression with pathologic stage, gender, age or tumor size in lung cancer patients (P > 0.05). Conclusion: LHX6 down-regulation may induce EGFR-TKIs resistance and increase the migration ability of HCC827/ER cells via activation of the Wnt/β-catenin pathway.
CITATION STYLE
Wang, Q., Liao, J., He, Z., Su, Y., Lin, D., Xu, L., … Lin, J. (2020). Lhx6 affects erlotinib resistance and migration of EGFR-mutant non-small-cell lung cancer HCC827 cells through suppressing wnt/β-catenin signaling. OncoTargets and Therapy, 13, 10983–10994. https://doi.org/10.2147/OTT.S258896
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