Abstract
BackgroundCircular RNAs (circRNAs) are involved in diverse processes that drive cancer development. However, the expression landscape and mechanistic function of circRNAs in osteosarcoma (OS) remain to be studied.MethodsBioinformatic analysis and high-throughput RNA sequencing tools were employed to identify differentially expressed circRNAs between OS and adjacent noncancerous tissues. The expression level of circ_001422 in clinical specimens and cell lines was measured using qRT-PCR. The association of circ_001422 expression with the clinicopathologic features of 55 recruited patients with OS was analyzed. Loss- and gain-of-function experiments were conducted to explore the role of circ_001422 in OS cells. RNA immunoprecipitation, fluorescence in situ hybridization, bioinformatics database analysis, RNA pulldown assays, dual-luciferase reporter assays, mRNA sequencing, and rescue experiments were conducted to decipher the competitive endogenous RNA regulatory network controlled by circ_001422.ResultsWe characterized a novel and abundant circRNA, circ_001422, that promoted OS progression. Circ_001422 expression was dramatically increased in OS cell lines and tissues compared with noncancerous samples. Higher circ_001422 expression correlated with more advanced clinical stage, larger tumor size, higher incidence of distant metastases and poorer overall survival in OS patients. Circ_001422 knockdown markedly repressed the proliferation and metastasis and promoted the apoptosis of OS cells in vivo and in vitro, whereas circ_001422 overexpression exerted the opposite effects. Mechanistically, competitive interactions between circ_001422 and miR-195-5p elevated FGF2 expression while also initiating PI3K/Akt signaling. These events enhanced the malignant characteristics of OS cells.ConclusionsCirc_001422 accelerates OS tumorigenesis and metastasis by modulating the miR-195-5p/FGF2/PI3K/Akt axis, implying that circ_001422 can be therapeutically targeted to treat OS.
Highlights
Circular RNAs are involved in diverse processes that drive cancer development
Identification and characterization of circ_001422 in OS To investigate the potential involvement of circRNAs in OS, three matched OS samples and adjacent noncancerous tissues were subjected to high-throughput sequencing analysis
The top ten most upregulated and downregulated circRNAs are presented in the cluster heatmap (Fig. 1a). By combining these results with the circRNA annotation in the circBase database, we found that circ_001422 is located on chromosome 4, has a length of 1703 bp and is generated by circularization of exons 2–7 of the host gene Nuclear receptor binding SET domain protein 2 (NSD2)
Summary
Circular RNAs (circRNAs) are involved in diverse processes that drive cancer development. The expression landscape and mechanistic function of circRNAs in osteosarcoma (OS) remain to be studied. Osteosarcoma (OS) is the most prevalent primary malignant bone neoplasm causing substantial morbidity in adolescents and children [1]. It originates from mesenchymal cells and is characterized by rapid infiltrating growth, early lung metastasis and a high recurrence rate [2]. Studies have shown that the overall 5-year survival rate of patients with localized OS ranges between 65 and 75% and is only 20% for those with recurrent and metastatic tumors [3]. Despite advances in OS treatment approaches such as adjuvant chemotherapy and surgical resection, the survival rates have plateaued in the last 3 decades and are less than satisfactory [4]. Molecular studies aiming to identify promising therapeutic targets for OS are urgently needed
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