title: Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer.
abstract: 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.
authors: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Hua
authors: H
authors: Shen
authors: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Fang
authors: F
authors: Zhu
authors: Department of Cardiothoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Jinyuan
authors: J
authors: Liu
authors: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Tongpeng
authors: T
authors: Xu
authors: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Dong
authors: D
authors: Pei
authors: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Rong
authors: R
authors: Wang
authors: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Yingying
authors: Y
authors: Qian
authors: Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Qi
authors: Q
authors: Li
authors: Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Lin
authors: L
authors: Wang
authors: Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Zhumei
authors: Z
authors: Shi
authors: Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Jitai
authors: J
authors: Zheng
authors: Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Qiudan
authors: Q
authors: Chen
authors: Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Binghua
authors: B
authors: Jiang
authors: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors: Yongqian
authors: Y
authors: Shu
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D016019:Survival Analysis
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077156:Gefitinib