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Objectives  Previous studies showed overexpression of ABCG2 in a variety of tumor tissues, which could potentially indicate the probability of chemotherapy resistance. This study aimed to reveal the role of ABCG2 in the development of chemotherapy resistance and the prognosis of osteosarcoma (OS).    Methods  Sixty-eight OS patients were included in this study. Tumor tissues were collected for each patient during surgery. DOX-resistant OS cell lines were induced by consecutive exposure of gradually increasing concentration of DOX to the parental cell lines. Lentivirus was used for the knockdown of ABCG2 in OS cells. Cells were treated with the gradient concentration of DOX, and the viability was assessed by CCK8 assay. Total RNA was isolated from the tumor tissues or tumor cells, and the expression of ABCG2 was analyzed by qPCR. The relationship between ABCG2 expression and clinicopathological characteristics of the patients was analyzed using Student’s  t  test or the Chi-square test. The overall survival time was calculated by the Kaplan-Meier method and analyzed by the log-rank test.  p  < 0.05 was considered statistically significant.    Results  DOX-resistant OS cells were successfully established through continuous exposure to DOX. Forty-eight hours after DOX exposure, the IC 50 value of DOX-resistant HOS cells and DOX-resistant U2OS was 3.5 μM and 3.25 μM, respectively. By contrast, those of the untreated HOS and U2OS cells were 1.15 μM and 0.93 μM, respectively ( p  < 0.01). The mRNA expression level of ABCG2 was significantly increased in DOX-resistant cell lines. The CCK-8 assay showed that the DOX-resistant HOS cells and DOX-resistant U2OS cells transfected with ShABCG2 were more sensitive to the DOX treatment than those transfected with ShCtrl. Analysis of gene expression in OS tissues showed remarkably higher expression of ABCG2 as compared with adjacent normal tissues ( p  < 0.01). Patients with high expression level of ABCG2 had obviously decreased overall survival time than the patients with normal expression ( p  < 0.01).    Conclusions  ABCG2 expression level was significantly associated with the resistance to chemotherapy and the overall survival of OS patients. ABCG2 may be a promising therapeutic target for OS patients.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13018-021-02204-z.

High expression of ABCG2 is associated with chemotherapy resistance of osteosarcoma