MiR-200c-3p suppression is associated with development of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer via a mediating epithelial-to-mesenchymal transition (EMT) process

Article type: Research Article

Authors: Wang, Hsin-Yi^{a; b; c} | Liu, Yi-Nan^d | Wu, Shang-Gin^d | Hsu, Chia-Lang^e | Chang, Tzu-Hua^d | Tsai, Meng-Feng^f | Lin, Yen-Ting^{b; d} | Shih, Jin-Yuan^{b; d; *}

Affiliations: [a] Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan | [b] Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan | [c] Thoracic Medicine Center, Department of Medicine and Surgery, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan | [d] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan | [e] Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan | [f] Department of Biomedical Sciences, Da-Yeh University, Changhua, Taiwan

Correspondence: [*] Corresponding author: Jin-Yuan Shih, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan. Tel.: +886 2 2312 3456 ext. 62905; Fax: +886 2 2358 2867; E-mail: [email protected].

Abstract: BACKGROUND:EGFR-mutant lung cancer inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). OBJECTIVE: To investigate the clinical relevance of microRNAs (miRNAs) in TKI therapy response and resistance. METHODS: We performed a miRNA PCR array analysis and used The Cancer Genome Atlas (TCGA) database to identify potential miRNAs related to EGFR TKIs resistance. We then correlated miRNA expression in 70 surgical and 50 malignant pleural effusion specimens with patient outcomes in those with non-small cell lung carcinoma. Molecular manipulation was performed in EGFR mutant lung cancer cells to assess the effect of miR-200c-3p on cell migratory ability and EGFR-TKI sensitivity. RESULTS: We identified miR-200c-3p and miR-203a-3p as potential EGFR TKI resistance regulators via their modulation of epithelial-to-mesenchymal transition (EMT). MiR-200c-3p and miR-203a-3p were down-regulated in EGFR TKI-resistant cell lines. Progression-free survival (PFS) with EGFR-TKI treatment of patients with high miR-200c-3p expression, but not miR-203a-3p, in the specimens was significantly longer than that of patients with low expression. MiR-200c-3p overexpression inhibited the EMT process in EGFR TKI resistance cell lines and promoted cell death. MiR-200c-3p silencing in EGFR TKI sensitive cell lines increased drug resistance. CONCLUSION: MiR-200c-3p plays a role in sensitivity to EGFR TKIs via modulating EMT process.

Keywords: Erlotinib, gefitinib, non-small cell lung cancer, miR-200c-3p, miR-203a-3p, tyrosine kinase inhibitors

DOI: 10.3233/CBM-191119

Journal: Cancer Biomarkers, vol. 28, no. 3, pp. 351-363, 2020