Abstract
ObjectivesPrevious 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).MethodsSixty-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.ResultsDOX-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).ConclusionsABCG2 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.
Highlights
Osteosarcoma (OS) is the most common malignant bone tumor characterized by a high incidence of distant metastasis [1, 2]
We aimed to investigate the role of ABCG2 in the development of doxorubicin (DOX) resistance and the prognosis of OS
ABCG2 was overexpressed in DOX-resistant OS cells Figure 1 showed that DOX-resistant OS cells were successfully established through continuous exposure to DOX
Summary
Osteosarcoma (OS) is the most common malignant bone tumor characterized by a high incidence of distant metastasis [1, 2]. Before the advent of neo-adjuvant chemotherapy, OS patients undergoing amputation or reconstruction surgery had low 5-year survival rates averaging approximately 15– 20% [3, 4]. Benefited from the multi-agent neo-adjuvant chemotherapy, the 5-year survival rate rises up to 70% for patients with non-metastatic OS [5]. It is noteworthy that patients with poor survival rate showed worse responsiveness to chemotherapy. Different approaches have been applied to investigate the mechanisms involved in chemoresistance of OS [6, 7]. It was speculated that intrinsic gene expression differences may account for the low responsiveness to chemotherapy, while the precise underlying mechanisms remain poorly understood. Identification of genes associated with chemoresistance is of great importance to personalize an effective regimen of chemotherapy
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