Abstract
BackgroundCircRNA CNST (circ-CNST) is a newly identified biomarker for prognosis of osteosarcoma (OS). However, its role in OS progression remains to be well documented.MethodsExpression of circ-CNST, microRNA (miR)-578, lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1) was detected by quantitative real-time polymerase chain reaction and Western blotting. The physical interaction was confirmed by dual-luciferase reporter assay. Cell behaviors and glycolysis were measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry, transwell assays, xenograft experiment, and commercial kits.ResultsCirc-CNST was upregulated in human OS tissues and cells, accompanied with downregulation of miR-578 and upregulation of LDHA and PDK1. There were negative correlations between miR-578 expression and circ-CNST or LDHA/PDK1 in OS tissues. Moreover, high circ-CNST/LDHA/PDK1 or low miR-578 might predict shorter overall survival, advanced TNM stages, and lymph node metastasis. Physically, miR-578 was targeted by circ-CNST, and miR-578 could target LDHA/PDK1. Functionally, blocking circ-CNST and restoring miR-578 enhanced apoptosis rate and suppressed cell proliferation, colony formation, migration, and invasion in 143B and U2OS cells, accompanied with decreased glucose consumption, lactate production, and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio. Furthermore, in vivo growth of U2OS cells was retarded by silencing circ-CNST. Depletion of miR-578 could counteract the suppressive role of circ-CNST deficiency in 143B and U2OS cells, and restoring LDHA or PDK1 partially reversed the role of miR-578 inhibition as well.ConclusionCirc-CNST knockdown could antagonize malignant behaviors and glycolysis of OS cells by regulating miR-578-LDHA/PDK1 axes.
Highlights
Osteosarcoma (OS), arising from transformed mesenchymal cells, is the most frequent primary bone tumor ranging from children to adolescents and young adults [1]
Circ-CNST was an upregulated circRNA in OS patients and cells Even though expression of circ-CNST in OS had once been identified, it was further validated in this present study
Chi-square test confirmed that circ-CNST level was significantly correlated with clinicopathologic features of OS patients, including TNM stage, lymph node metastasis, and tumor size (Table 1)
Summary
Osteosarcoma (OS), arising from transformed mesenchymal cells, is the most frequent primary bone tumor ranging from children to adolescents and young adults [1]. Metabolic reprogramming in cancer is manifested by persistent aerobic glycolysis and suppression of mitochondrial function, which is called the Warburg effect, a hallmark of many malignant tumors including OS [2]. The generation of adenosine triphosphate (ATP) is less efficient, tumor cells benefit from aerobic glycolysis in growth, metastasis, and drug resistance [3, 4]. Treatment for OS has been improved, the likelihood of survival remains low for OS patients with metastasis and recurrence. Pulmonary metastasis is observed in 30–35% of OS patients after initial treatment for 2 to 3 years [7]. It is necessary to understand the molecular mechanism of OS progression and glycolysis to identify more effective therapeutic targets. Its role in OS progression remains to be well documented
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