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Tumor microenvironment is known to play important roles in tumor progression. Many therapies, targeting the tumor microenvironment, are designed and applied in the clinic. One of these approaches is in situ antitumor therapy. This way, bacteria, antibodies, plasmid DNA, viruses, and cells are intratumorally delivered into the tumor site as “in‐situ antitumor vaccine,” which seeks to enhance immunogenicity and generate systemic T cell responses. In addition, this intratumoral therapy can alter the tumor microenvironment from immunosuppressive to immunostimulatory while limiting the risk of systemic exposure and associated toxicity. Contemporarily, promising preclinical results and some initial success in clinical trials have been obtained after intratumoral therapy.

Circular RNA (circRNA) is a class of endogenous noncoding RNA (ncRNA), presenting as a special covalent closed loop without a 5′ cap or 3′ tail, maintaining resistance to RNA exonuclease and keeping high stability. Although lowly expressed in most situations, circRNA makes an active difference in regulating physiological or pathological processes by modulating gene expression by regulation of transcription, protein, and miRNA functions through various mechanisms in particular tissues. Recent studies have demonstrated the roles of the miRNA–circRNA network in the development of several bone diseases such as osteoporosis, a multiple‐mechanism disease resulting from defective bone quality and low bone mass, osteoarthritis, whose main pathomechanism is inflammation and articular cartilage degradation, as well as osteosarcoma, known as one of the most common bone cancers. However, the specific mechanism of how circRNA along with miRNA influences those diseases is not well documented, showing potential for the development of new therapies for those bone diseases.

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ObjectivesIncreasing evidence indicated circRNAs were involved in stem cells osteogenesis differentiation. Herein, we aimed to clarify the role of hsa‐circ‐0107593 during the osteogenesis process of human adipose‐derived stem cells (hADSCs) and the underlying mechanisms.MethodsThe ring structure of hsa‐circ‐0107593 was confirmed using RNase R treatment and Sanger sequencing. Nucleoplasmic separation and fluorescence in situ hybridization detected hsa‐circ‐0107593 distribution. Lentivirus and siRNA were used to modulate the expression of hsa‐circ‐0107593, and the binding relationship between hsa‐circ‐0107593 and miR‐20a‐5p was verified by luciferase assay and RNA immunoprecipitation. We detected the osteogenic activity of hADSCs through alkaline phosphatase staining, alizarin red S staining, real‐time polymerase chain reaction (RT‐PCR), western blot, and cellular immunofluorescence experiment. In vivo, micro‐computed tomography was performed to analyze bone formation around skull defect.ResultsRT‐PCR results exhibited that hsa‐circ‐0107593 was downregulated while miR‐20a‐5p was upregulated during hADSCs osteogenesis. In vivo and in vitro experiments results indicated that knocking down hsa‐circ‐0107593 promoted the osteogenic differentiation of hADSCs, while overexpression of hsa‐circ‐0107593 showed an inhibitory effect on hADSCs osteogenic differentiation. In vitro experiment results showed hsa‐circ‐0107593 acted as a hADSCs osteogenic differentiation negative factor for it inhibited the suppressing effect of miR‐20a‐5p on SMAD6.ConclusionKnocking down hsa‐circ‐0107593 acts as a positive factor of the osteogenic differentiation of hADSCs via miR‐20a‐5p/SMAD6 signaling.