Circular RNA circ_001422 Promotes Progression and Metastasis of Osteosarcoma via the miR-195-5p/FGF2/PI3K/Akt Axis

Abstract

BackgroundCircular RNAs (circRNAs) are involved in diverse processes that drive cancer development. Nevertheless, the expression landscape and mechanistic function of circRNAs in osteosarcoma (OS) remain to be studied.MethodsBioinformatics analysis and high-throughput RNA sequencing tools were employed to determine differentially expressed circRNAs between OS and adjacent healthy tissues. The expression levels of circ_001422 in clinical specimens and cell lines were measured using qRT-PCR. A total of 55 OS patients were recruited to analyze the association of circ_001422 expression with clinicopathologic features. Loss- and gain-of-function tests were conducted to explore the role of circ_001422 in OS cells. RNA immunoprecipitation, fluorescent in situ hybridization, bioinformatics databases, RNA pull-down assay, dual-luciferase reporter assay, mRNA sequencing, and rescue experiments were conducted to decipher the competitive endogenous RNAs regulatory network dominated by circ_001422.ResultsWe characterized a novel and abundant circRNA, circ_001422, which promoted the progression of OS. Circ_001422 expression was dramatically higher in OS cell lines and tissues relative to normal samples. Increased circ_001422 correlated with more advanced clinical stage, larger tumor size, more distant metastases and poorer overall survival of OS patients. Knockdown of circ_001422 markedly repressed proliferation and metastasis and promoted apoptosis of OS cells in vivo and in vitro, whereas overexpression of circ_001422 exerted an opposite effect. Mechanistically, competitive interactions between circ_001422 and miR-195-5p elevated the expression of FGF2 while also initiating the PI3K/Akt signaling pathway. These events enhanced the malignant characteristics of OS cells.ConclusionsCirc_001422 accelerates OS tumorigenesis and metastasis through modulating the miR-195-5p/FGF2/PI3K/Akt axis, implying that circ_001422 could be therapeutically targeted to treat OS patients.

Circ_001422 aggravates osteosarcoma progression through targeting miR-497-5p/E2F3 axis

“…Additionally, circ_0000658 level decreased within osteosarcoma, while circ_0000658 down-regulation suppressed OS malignant biological behavior as a tumor suppressor gene [31] . As found by a previous study, circ_001422 was con rmed to promote OS metastasis and development by miR-195-5p/FGF2/PI3K/Akt axis [14] . This experiment also con rmed that circ_001422 was abnormally increased within OS, while circ_001422 upregulation within tissues was tightly associated with high patient clinical stage as well as metastatic events.…”

“…MiR-497-5p serves as circ_001422's target circRNAs often play a role of miRNA sponges for regulating the expression of miRNAs, thereby participating in cellular functions [13,14] . The StarBase database estimated miR-497-5p containing circ_001422 binding sites (Figure 2A).…”

“…As an important participant in the ceRNA network, circRNAs can adsorb miRNAs through sponges, thereby affecting the latter downstream target gene levels, resulting in changes in cell phenotypes [12][13][14] . Here, we have demonstrated miR-497-5p as circ_001422's target, while E2F3 as miR-497-5p's target.…”

“…Circ-LRP6 expression increases in OS cells as well as tissues, whereas its down-regulation can inhibit the OS cell growth, migration and invasion by miR-141-3p/HDAC4/HMGB1 axis [13] . Circ_001422, the newly reported circRNA, has been reported to promote OS tumorigenesis [14] . However, the mechanism of the involvement of circ_001422 in OS is not completely clear at present.…”

Bioinformatics analysis of lncRNAs in the occurrence and development of osteosarcoma

“…The circular RNA circTADA2A promotes the progression and metastasis of OS by sponging miR-203A-3p and regulating CREB3 expression (25). Circ_001422 accelerates OS oncogenesis and metastasis by regulating the miR-195-5p/FGF2/PI3K/Akt axis, which suggests that Circ_001422 can be the target for OS therapy (26).…”