Icotinib-resistant HCC827 cells produce exosomes with mRNA MET oncogenes and mediate the migration and invasion of NSCLC

Yiming Yu,Chaofen Li,Maidinaimu Abudula,Zhongbo Chen,Yichen Chen,Yun Zhang

doi:10.1186/s12931-019-1202-z

Abstract

BackgroundIcotinib has been widely used in patients with non-small cell lung cancer (NSCLC), and have significantly enhanced the overall survival rate of NSCLC patients. However, acquired drug resistance limits its clinical efficacy. Tumor cell-derived exosomes have been reported to participate in various biological processes, including tumor invasion, metastasis and drug resistance.Materials and methodsIn the present study, drug resistance was measured by MTT assay. Exosomes were extracted from the cell supernatant using ultracentrifugation and identified by exosomal marker. HCC827 cells were treated with exosomes derived from icotinib-resistant (IR) HCC827 to observe the invasion and migration of parent cells. The expression of exo-mRNA was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-PCR). In addition, 10 exo-mRNAs detecting from the plasma and bronchoalveolar lavage fluid (BALF) of NSCLC patients with icotinib treatment were used to establish a new drug resistant-warning formula.ResultsThe oncogene MET into exosomes was identified from icotinib-resistant lung cancer cells, and this was also presented in exosomes in NSCLC patients diagnosed with cancer metastasis after icotinib treatment. The knockdown of MET in exosomes significantly decreased the ability of invasion and migration in HCC827 cells.ConclusionIt was suggested that MET might be specifically package and transferred by exosomes to modify the invasion and migration ability of the surrounding icotinib-sensitive cells.

Highlights

Icotinib has been widely used in patients with non-small cell lung cancer (NSCLC), and have significantly enhanced the overall survival rate of NSCLC patients
The oncogene MET into exosomes was identified from icotinib-resistant lung cancer cells, and this was presented in exosomes in NSCLC patients diagnosed with cancer metastasis after icotinib treatment
Establishment of the icotinib-resistance HCC827 IR cell model Human NSCLC HCC827 cells with the deletion of exon19 of epidermal growth factor receptor (EGFR) was used to establish the new model of acquired resistance to icotinib

Summary

Introduction

Icotinib has been widely used in patients with non-small cell lung cancer (NSCLC), and have significantly enhanced the overall survival rate of NSCLC patients. Platinum-based combination chemotherapy has a survival rate of less than one year for the majority of patients with advanced NSCLC [3] This disappointing result has prompted the search for new drugs and treatments. Several studies have reported that plasmatic exosomal proteins like CD91,CD317 and EGFR in NSCLC patients can be promising diagnostic biomarkers [9,10,11,12]. It has been showed in a study that with the release of exosomes by NSCLC A459 cells during cisplatin stimulation, the sensitivity of A459 cells to cisplatin has decreased. The involvement of exosomes in the development of resistance to icotinib and tumor metastasis in lung cancer cells remains unclear

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Discussion

Conclusion