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MicroRNA-150 functions as an antioncogenic regulator in osteosarcoma.

ABSTRACT: Numerous studies have demonstrated that microRNAs (miRs) are involved in several physiological and pathological processes, and participate in cancer initiation and progression. The abnormal expression of miR-150 has been reported in numerous types of human cancer. However, at present there are no studies of miR-150 in osteosarcoma (OS). Reverse transcription-quantitative polymerase chain reaction was performed to measure miR-150 expression levels in OS tissues and cell lines. Subsequent to transfection with miR-150 mimics or zinc finger E-box binding homeobox 1 (ZEB1) small interfering RNA, an MTT assay, Transwell migration and invasion assays, western blotting and a Dual-Luciferase reporter assay were performed in human OS cell lines. The present study revealed that miR-150 was downregulated in OS tissues and cell lines. In addition, the expression levels of miR-150 were correlated with the clinical stage and degree of distant metastasis of patients with OS. In addition, ZEB1 was identified as a direct target of miR-150 in vitro. In conclusion, miR-150 targeted ZEB1 to function as an antioncogenic regulator in OS. These findings elucidated a novel underlying mechanism for the pathogenic process in OS carcinogenesis and progression, and may provide novel targeted therapeutic regimens for patients with OS.

SUBMITTER: Xu J

PROVIDER: S-EPMC5530169 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundDistraction osteogenesis (DO) is a highly efficacious form of reconstructive bone regeneration, but its clinical utility is limited by the prolonged period required for bone consolidation to occur. Understanding the mechanistic basis for DO and shortening this consolidation phase thus represent promising approaches to improving the clinical utility of this procedure.MethodsA mandibular DO (MDO) canine model was established, after which small RNA sequencing was performed to identify relevant molecular targets genes. Putative miRNA target genes were identified through bioinformatics and confirmed through qPCR, Western blotting, and dual-luciferase reporter assays. Peripheral blood samples were collected to isolate serum and endothelial colony-forming cells (ECFCs) in order to measure miR-205, NOTCH2, and angiogenic cytokines expression levels. Lentiviral constructs were then used to inhibit or overexpress miR-205 and NOTCH2 in isolated ECFCs, after which the angiogenic activity of these cells was evaluated in migration, wound healing, proliferation, tube formation, and chick chorioallantoic membrane (CAM) assay. Autologous ECFCs transfected to knockdown miR-205 and were injected directly into the distraction callus. On days 14, 28, 35 and 42 after surgery, bone density was evaluated via CBCT, and callus samples were collected and evaluated via histological staining to analyze bone regeneration and remodeling.ResultsMiR-205 was identified as being one of the miRNAs that was most significantly downregulated in MDO callus samples. Downregulation of miR-205 was also observed in DO-ECFCs and serum of animals undergoing MDO. Inhibiting miR-205 markedly enhanced angiogenesis, whereas overexpressing miR-205 had the opposite effect in vitro. Importantly, NOTCH2, which is a unique regulator in bone angiogenesis, was identified as a miR-205 target gene. Consistent with this regulatory relationship, knocking down NOTCH2 suppressed angiogenesis, and transduction with a miR-205 inhibitor lentivirus was sufficient to rescue angiogenic activity. When ECFCs in which miR-205 had been inhibited were transplanted into the MDO callus, this significantly bolstered osteogenesis, and remodeling in vivo.ConclusionsMiR-205 is a significant regulator of the MDO process, and inhibiting this miRNA can accelerate MDO-related mineralization. Overall, these results offer new insights into the mechanistic basis for this procedure, highlighting potential targets for therapeutic clinical intervention.

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MicroRNA-150 functions as an antioncogenic regulator in osteosarcoma.

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