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Qiang Wang,1 Jinrong Liao,2 Zhiyong He,1,3 Ying Su,2 Dong Lin,1 Ling Xu,1 Haipeng Xu,1 Jinghui Lin1 1 Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, People’s Republic of China; 2Department of Radiobiology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, People’s Republic of China; 3Fujian Provincial Key Laboratory of Translation Cancer Medicine, Fuzhou 350014, People’s Republic of ChinaCorrespondence: Zhiyong HeDepartment of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, No. 420 Fuma Road, Fuzhou City, Fujian Province 350014, People’s Republic of ChinaEmail zhiyonghecn@sina.comBackground: 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.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