CircRNA CDR1as/miR-7 signals promote tumor growth of osteosarcoma with a potential therapeutic and diagnostic value

Abstract

BackgroundThe circular RNA (circRNA) antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as)/micro RNA-7(miR-7) signal axis has been investigated in many diseases via regulation of the target genes of miR-7, which participates in the carcinogenesis and metastasis. However, the clinical role and function of CDR1as/miR-7 pathway in osteosarcoma (OS) remain to be identified.Materials and methodsNoncancerous bone tissues (n=18) and OS tissues (n=38) were used to determine the expressions and roles of CDR1as and miR-7. We knocked down the expression of CDR1as via siRNAs in OS cell lines to analyze its function in vitro and in vivo.ResultsCDR1as was upregulated in OS tissues with significant diagnostic value (cutoff value: 1.613). OS patients with high tumor size, Enneking stage, and distant metastasis have high CDR1as levels, but the miR-7 as tumor suppressor negatively correlated with CDR1as. Inhibition of CDR1as in OS cell lines U2OS and MG63 with high CDR1as levels, leading to de-repressed miR-7 levels, impaired cell vitality and increased apoptosis and G1/S arrest in parallel with reduced ability of cell migration, which, however, could be restored by miR-7 inhibitor. Mechanistically, knockdown of CDR1as could restore the availability of miR-7 and inhibit the target genes of miR-7 including EGFR, CCNE1, PI3KCD, and RAF1. Moreover, CDR1as also upregulated N-cadherin and inhibited E-cadherin to promote the epithelial–mesenchymal transition via miR-7 for cell migration. CDR1as inhibition in vivo also induced tumor regression with decreased PCNA levels, and miR-7 inhibitor could reverse these effects via upregulation of EGFR, CCNE1, PI3KCD, and RAF1. The expressions of these genes were confirmed to be higher in CDR1as-high OS samples than in CDR1as-low OS samples.ConclusionThese findings suggested that the CDR1as/miR-7 signal axis could be the molecular target for the treatment of OS.

Functional roles of circular RNAs during epithelial-to-mesenchymal transition

“…Furthermore, the circRNA CDR1as/miR-7 pathway regulates the EMT phenotype. Furthermore, a miR-7 inhibitor can enhance the metastatic ability of HCC and OS cells [123,124].…”

Diagnostic and Prognostic Significance of Dysregulated Expression of Circular RNAs in Osteosarcoma

“…Moreover, 22 studies were further eliminated with a variety of reasons, including ve studies not related to circRNAs or osteosarcoma, six studies did not report outcomes, two reviews and case reports, four animal studies, and ve lack of extractable data. Finally, 26 studies comprising 1,652 osteosarcoma cases were enrolled in this quantitative study, with 18 on clinicopathological features, ten on diagnosis [13,18,19,21,24,[30][31][32][33][34] [12,14,18,19,[32][33][34][36][37][38][39][40], whereas other two studies on downregulated circRNAs applying ≥ 18 or < 18 years old to separate enrolled patients [13,30]. In consideration of the consistency, only these studies with common cut-off value were included in the following meta-analysis with regard to patients' age.…”

“…The duration for follow-up ranged from 40 to 125. For diagnostic assay, ten studies with data on sensitivity, speci city and AUC [13,18,19,21,24,[30][31][32][33][34]. The quality of studies was evaluated by QUADAS II and NOS scores.…”

“…Additionally, a small set of oncogenic circRNAs with different diagnosis e ciency were synthesized in order to explore the combination panel of certain circRNAs with even higher diagnostic potential, which may facilitate the clinical application of the circRNAs for diagnosis. Among them, the pooled analysis containing circPVT1, circ_0081001, and CDR1as, has the highest diagnostic e ciency [18,19,33]. As shown in Figure S1, the forest plot of the pooled DOR, SENS and SPEC of these three circRNAs panel were 32.21 (95%: 9.51-109.1), 0.85 (95% CI: 0.78-0.90), and 0.83 (95% CI: 0.71-0.91), respectively.…”

Construction of a circRNA-miRNA-mRNA network based on competitive endogenous RNA reveals the function of circRNAs in osteosarcoma

“…Song et al found that hsa_circ_0001564 acts as a miR-29c-3p sponge to cause tumourigenesis and may serve as a potential biomarker for OS [16]. In addition, a related study found that circRNA CDR1as/miR-7 signalling promotes tumour growth in OS, with potential therapeutic and diagnostic value [17]. These studies indicate that cir-cRNAs play an important role in the development and progression of OS.…”