Epigenetic silencing of miR-483-3p promotes acquired gefitinib resistance and EMT in EGFR-mutant NSCLC by targeting integrin β3.

Abstract

All lung cancers patients with epidermal growth factor receptor (EGFR) mutation inevitably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In up to 30% of cases, the mechanism underlying acquired resistance remains unknown. MicroRNAs (miRNAs) is a group of small non-coding RNAs commonly dysregulated in human cancers and have been implicated in therapy resistance. The aim of this study was to understand the roles of novel miRNAs in acquired EGFR TKI resistance in EGFR-mutant non-small cell lung cancer (NSCLC). Here, we reported the evidence of miR-483-3p silencing and epithelial-to-mesenchymal transition (EMT) phenotype in both in vitro and in vivo EGFR-mutant NSCLC models with acquired resistance to gefitinib. In those tumor models, forced expression of miR-483-3p efficiently increased sensitivity of gefitinib-resistant lung cancer cells to gefitinib by inhibiting proliferation and promoting apoptosis. Moreover, miR-483-3p reversed EMT and inhibited migration, invasion, and metastasis of gefitinib-resistant lung cancer cells. Mechanistically, miR-483-3p directly targeted integrin β3, and thus repressed downstream FAK/Erk signaling pathway. Furthermore, the silencing of miR-483-3p in gefitinib-resistant lung cancer cells was due to hypermethylation of its own promoter. Taken together, our data identify miR-483-3p as a promising target for combination therapy to overcome acquired EGFR TKI resistance in EGFR-mutant NSCLC.

• Authors: Jinnan Yue, Dacheng Lv, Caiyun Wang, Ling Li, Qingnan Zhao, Hongzhuan Chen, Lu Xu
• Journal: Oncogene (Oncogene) Vol. 37 Issue 31 Pg. 4300-4312 (08 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29717264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Integrin beta3
• MIRN483 microRNA, human
• MicroRNAs
• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors
• Gefitinib

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Drug Resistance, Neoplasm (genetics)
• Epigenesis, Genetic (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• ErbB Receptors (genetics)
• Gefitinib (pharmacology)
• Gene Silencing (physiology)
• Humans
• Integrin beta3 (genetics)
• Lung Neoplasms (drug therapy, genetics)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Protein Kinase Inhibitors (pharmacology)
• Xenograft Model Antitumor Assays