Abstract
Drug resistance is one of the main factors limiting the efficacy of chemotherapy in patients with laryngeal cancer; thus, it is important to investigate the drug resistance of laryngeal cancer. In the present study, the mechanism of the regulation of drug resistance in laryngeal cancer cells by ATP-binding transporter G2 (ABCG2) that is present in the extracellular vesicles (EVs) released by drug-resistant cells was studied in vivo and in vitro. A cisplatin (CDDP)-resistant cell line (AMC-HN-8/CDDP) was established from AMC-HN-8 cells by continuous exposure to increasing concentrations of CDDP. The EVs extracted from the culture medium of AMC-HN-8/CDDP and AMC-HN-8 cells were termed EVs1 and EVs2, respectively. Following 48-h treatment of AMC-HN-8 cells with EVs1 or EVs2, the cells were designated as AMC-HN-8-EVs1 or AMC-HN-8-EVs2. Nude mice bearing AMC-HN-8-EVs1 and AMC-HN-8 cell-derived xenograft tumors were established to detect the effects of EVs on drug resistance. The resistance index of AMC-HN-8/CDDP cells to CDDP was 5.60, which was determined by the MTT assay. The mRNA and protein expression levels of ABCG2 in AMC-HN-8/CDDP cells and EVs1 were significantly higher compared with those in AMC-HN-8 cells and EVs2, respectively (P<0.01). The ABCG2 mRNA and protein levels, and the proliferation index of AMC-HN-8-EVs1 cells were significantly higher compared with those of AMC-HN-8-EVs2 and AMC-HN-8 cells (P<0.01), whereas the apoptotic rate was significantly lower (P<0.01). The mean volume of subcutaneous tumor xenografts in the test group (inoculated with AMC-HN-8-EVs1 cells and intraperitoneally injected with 3 mg/kg CDDP) was significantly higher compared with that in the control group (inoculated with AMC-HN-8 cells and intraperitoneally injected with 3 mg/kg CDDP) (P<0.01), whereas the apoptotic rate of tumor cells was significantly lower (P<0.01). The ABCG2 mRNA and the protein expression levels in the tumor cells of the test group were significantly higher compared with those in the blank (inoculated with AMC-HN-8 cells and was intraperitoneally injected with normal saline) and control groups (P<0.01). The high expression levels of ABCG2 in laryngeal carcinoma cells affected the drug resistance of the cells. The EVs released by drug-resistant cells upregulated the expression of ABCG2 and induced drug resistance in laryngeal carcinoma cells, which may be dependent on the ABCG2 gene carried by the EVs.