CircRNA CDR1as/miR-7 signals promote tumor growth of osteosarcoma with a potential therapeutic and diagnostic value
Received 25 June 2018
Accepted for publication 11 August 2018
Published 23 October 2018 Volume 2018:10 Pages 4871—4880
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Professor Nakshatri
Bo Xu,1,* Tieyi Yang,1 Zhi Wang,1,* Yan Zhang,1 Shuyi Liu,1 Mingquan Shen2
1Department of Orthopaedics, Gongli Hospital of Pudong New Area, Shanghai, 200135, China; 2Department of Orthopaedics, Pudong New Area People’s Hospital affiliated to Shanghai University of Medicine and Health Sciences, Shanghai, 201200, China
*These authors contributed equally to this work
Background: The 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 methods: Noncancerous 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.
Results: CDR1as 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.
Conclusion: These findings suggested that the CDR1as/miR-7 signal axis could be the molecular target for the treatment of OS.
Keywords: CDR1as, miR-7, osteosarcoma, apoptosis, EMT
Corrigendum for this paper has been published
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