Abstract
The long noncoding RNA NR2F1-AS1 has been found to promote the development of hepatocellular carcinoma and endometrial cancer. In this study, we measured NR2F1-AS1 expression in osteosarcoma (OS), determined the involvement of NR2F1-AS1 in the malignant properties of OS, and investigated the underlying mechanisms. NR2F1-AS1 was found to be upregulated in OS tumors and cell lines. The increased NR2F1-AS1 level was closely associated with advanced clinical stage and distant metastasis in patients with OS. Patients with OS in an NR2F1-AS1 high-expression group demonstrated significantly shorter overall survival than did patients in an NR2F1-AS1 low-expression group. NR2F1-AS1 knockdown inhibited OS cell proliferation, migration, and invasion and promoted cell cycle arrest and apoptosis in vitro and slowed tumor growth in vivo. NR2F1-AS1 was found to function as a competing endogenous RNA by directly sponging microRNA-483-3p (miR-483-3p) and upregulating its target oncogene forkhead box A1 (FOXA1). Finally, rescue experiments revealed that knockdown of miR-483-3p and recovery of FOXA1 expression both attenuated the influence of the NR2F1-AS1 knockdown on OS cells. Thus, NR2F1-AS1 plays an oncogenic role in OS through sponging miR-483-3p and thereby upregulating FOXA1, suggesting an additional target for osteosarcoma therapeutics.
Highlights
Osteosarcoma (OS) is a highly malignant bone cancer that ranks as the most common primary human malignant tumor among children and adolescents [1]
Patients with OS in the NR2F1-AS1 highexpression group demonstrated shorter overall survival than did the patients in the NR2F1-AS1 low-expression group (Figure 1C, P = 0.022). These results indicated that NR2F1-AS1 might be closely associated with the malignancy of OS
Functional experiments on cell proliferation, apoptosis, cell cycle, migration, and invasion were conducted and the results demonstrated that the NR2F1-AS1 knockdown– mediated effects on HOS and U2OS cell proliferation (Figure 6B, P < 0.05), apoptosis (Figure 6C, P < 0.05), cell cycle (Figure 6D, P < 0.05), migration (Figure 6E, P < 0.05), and invasion (Figure 6F, P < 0.05) were substantially attenuated by the recovery of forkhead box A1 (FOXA1)
Summary
Osteosarcoma (OS) is a highly malignant bone cancer that ranks as the most common primary human malignant tumor among children and adolescents [1]. MicroRNAs (miRNAs, miRs) are short singlestranded noncoding RNA molecules [15] They participate in gene silencing and repress gene expression by directly interacting with the 3′ untranslated region (3′-UTRs) of target mRNAs, resulting in mRNA degradation and/or repression of translation [16]. We attempted to quantify NR2F1-AS1 levels in OS tumors and cell lines, determine its function in OS progression, and investigate its mechanism of action. These data may help to develop methods for the early diagnosis of OS and to identify effective therapeutic targets
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