Abstract
Background:
Gefitinib resistance has become a major obstacle for cancer therapy of non-small cell lung cancer (NSCLC). Exosome-mediated transfer of long noncoding RNAs (lncRNAs) is associated with the drug-resistance in various tumors. However, the role of NSCLC-specific exosomal lncRNAs remains largely unknown. The aim of this study is to explore the role of exosomal Hox transcript antisense intergenic RNA (HOTAIR) on gefitinib resistance in NSCLC.
Methods:
We investigated the expression of lncRNAs in 5 paired gefitinib-sensitive and gefitinib-resistant tissues of NSCLC by microarray analysis. The qRT-PCR analysis was to investigate the expression pattern of HOTAIR in gefitinib-resistant NSCLC patient tissues and cell lines. Then, we investigated the effects of HOTAIR on gefitinib resistance in vitro and in vivo.
Results:
In this study, we found HOTAIR was evidently up-regulated in both tissues and serum exosome of gefitinib-resistant NSCLC patients. Moreover, by knocking down HOTAIR, we found that HOTAIR promoted the proliferation of NSCLC cells in vitro, as well as inhibited cell apoptosis and cell sensitivity to gefitinib. Extracellular HOTAIR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminated gefitinib resistance. The expression level of HOTAIR from circulating exosomes is significantly higher in NSCLC patients with gefitinib resistance than those without gefitinib resistance. Mechanistically, bioinformatic analysis coupled with dual luciferase assay revealed that HOTAIR served as miR-216a sponge, and MAP1S was identified as a functional target of miR-216a.
Conclusions:
In conclusion, these data suggest that exosomal HOTAIR serves as an oncogenic role in gefitinib resistance of NSCLC cells CRC through activating miR-216a/MAP1S signaling pathway, providing a novel avenue for the treatment of NSCLC.