Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer

• Published in: PloS one Vol. 9; no. 7; p. e103305
• Main Authors: Shen, Hua, Zhu, Fang, Liu, Jinyuan, Xu, Tongpeng, Pei, Dong, Wang, Rong, Qian, Yingying, Li, Qi, Wang, Lin, Shi, Zhumei, Zheng, Jitai, Chen, Qiudan, Jiang, Binghua, Shu, Yongqian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.07.2014; Public Library of Science (PLoS)
• Subjects: AKT protein; Animals; Apoptosis; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Deactivation; Drug Resistance, Neoplasm; Epidermal growth factor; Epidermal growth factor receptors; Gefitinib; Gene Expression Regulation, Neoplastic - drug effects; HEK293 Cells; Hospitals; Humans; Immunoglobulins; Inactivation; Inhibitor drugs; Kinases; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lymphoma; Male; MAP Kinase Signaling System - drug effects; Medical prognosis; Medicine and Health Sciences; Metabolic pathways; Metastasis; Mice; Mice, Nude; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Mutation; Neoplasm Transplantation; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Overexpression; Pathology; Patients; Protein Kinase Inhibitors - administration & dosage; PTEN Phosphohydrolase - genetics; PTEN protein; Quinazolines - administration & dosage; Ribonucleic acid; RNA; Sensitivity; Survival Analysis; Targeted cancer therapy; Tissues; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0103305

Resistance to TKI treatment is a major obstacle in effective treatment of NSCLC. Besides EGFR mutation status, the mechanisms involved are largely unknown. Some evidence supports a role for microRNA 21 in modulating drug sensitivity of chemotherapy but its role in NSCLC TKI resistance still remains unexplored. This study aimed to investigate whether NSCLC miR-21 mediated resistance to TKIs also results from Pten targeting. Here, we show miR-21 promotes cancer by negatively regulating Pten expression in human NSCLC tissues: high miR-21 expression levels were associated with shorter DFS in 47 NSCLC patients; high miR-21/low Pten expression levels indicated a poor TKI clinical response and shorter overall survival in another 46 NSCLC patients undergoing TKI treatment. In vitro assays showed that miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERK pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AKT and ERK pathways, in vivo and in vitro. We propose alteration of miR-21/Pten expression as a novel mechanism for TKI resistance in NSCLC cancer. Our findings provide a new basis for using miR 21/Pten-based therapeutic strategies to reverse gefitinib resistance in NSCLC.