<p>LHX6 Affects Erlotinib Resistance and Migration of <em>EGFR</em>-Mutant Non-Small-Cell Lung Cancer HCC827 Cells Through Suppressing Wnt/β-Catenin Signaling</p>
Qiang Wang, Jinrong Liao, Zhiyong He, Ying Su, Dong Lin, Ling Xu, Haipeng Xu, Jinghui Lin
Abstract
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 IC 50 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. Keywords: non-small-cell lung cancer, epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI, LIM homeobox domain 6, LHX6, erlotinib, chemotherapy resistance, Wnt/β-catenin signaling Corrigendum for this paper has been published Further corrigendum has been published