Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer

// Hui Pan 1, * , Tao Jiang 1, * , Ningning Cheng 1 , Qi Wang 1 , Shengxiang Ren 1 , Xuefei Li 2 , Chao Zhao 2 , Limin Zhang 1 , Weijing Cai 1 , Caicun Zhou 1 1 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Yangpu District, Shanghai, China 2 Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University, Tongji University Medical School Cancer Institute, Shanghai, P. R. China * These authors contributed equally to this work Correspondence to: Caicun Zhou, email: caicunzhou_dr@163.com Keywords: long non-coding RNA, non-small-cell lung cancer, non-T790M mutation, acquired resistance, EGFR-TKIs Received: April 10, 2016 Accepted: June 13, 2016 Published: July 09, 2016 ABSTRACT Our previous study demonstrated that long non-coding RNA (lncRNA) BC087858 could stimulate acquired resistance to EGFR-TKIs in non-small cell lung (NSCLC) but the specific regulatory mechanism remained unknown. We aimed to explore the role and mechanism of lncRNA BC087858 on EGFR-TKIs acquired resistance. LncRNA BC087858 mRNA expression was detected by reverse transcription polymerase chain reaction in different NSCLC cell lines and tissues. The relationship between BC087858 expression and clinicopathological factors was performed by Cox multivariate regression analysis. Small-interfering RNA, flow cytometry and trans-well assay were conducted to explore the biological functions of BC087858. Western blotting was used to analyze the target proteins expression. Over-expression was observed in NSCLC cells and patients with acquired resistance to EGFR-TKIs and significantly associated with a shorter progression-free survival (PFS) (12.0 vs. 17.0 months, P = 0.0217) in tumors with respond to EGFR-TKIs. The significant relationship was not observed in patients with T790M mutation (median PFS 17.6 vs. 12.5 months, P = 0.522) but in patients with non-T790M (median PFS 8.0 vs. 18.25 months, P = 0.0427). Down-regulation of BC087858 could significantly promote PC9/R and PC9/G2 cells invasion ( P < 0.05; respectively). BC087858 knockdown restored gefitinib sensitivity in acquired resistant cells with non-T790M and inhibited the activation of the PI3K/AKT and MEK/ERK pathways and epithelial-mesenchymal transition (EMT) via up- regulating ZEB1 and Snail. In conclusion, LncRNA BC087858 could promote cells invasion and induce non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT via up- regulating ZEB1 and Snail in NSCLC.