Metabolic switch from oxidative phosphorylation to aerobic glycolysis, which is also called the Warburg effect, is a hallmark of osteosarcoma (OS) and leads to the enhancement of cell chemoresistance, growth, metastasis, and invasion. Emerging evidence indicates that long non-coding RNA (lncRNA) plays a crucial role in the Warburg effect of cancer cells. Here, we report that lncRNA KCNQ1OT1 was upregulated in OS. Meanwhile, functional experiments demonstrated that the KCNQ1OT1 facilitated proliferation and suppressed apoptosis of OS cells. In addition, KCNQ1OT1 contributed to the Warburg effect by stimulating aldolase A (ALDOA) expression. Furthermore, using bioinformatics analysis, luciferase reporter, RNA immunoprecipitation, and RNA pull-down assay, we identified that KCNQ1OT1 functions as a competing endogenous RNA (ceRNA) by sponging miR-34c-5p, which inhibited ALDOA expression by directly targeting its 3ʹUTR. Taken together, these data identified a key role of KCNQ1OT1 in glucose metabolism reprogramming of OS. Targeting the KCNQ1OT1/miR-34c-5p/ALDOA axis may be a potential therapeutic target in OS treatment.
Background: Electrospinning is a widely used technology that can produce scaffolds with high porosity and surface area for bone regeneration. However, the small pore sizes in electrospun scaffolds constrain cell growth and tissue-ingrowth. In this study, novel drugloading core-shell scaffolds were fabricated via electrospinning and freeze drying to facilitate the repair of tibia bone defects in rabbit models. Materials and Methods: The collagen core scaffolds were freeze-dried containing icariin (ICA)-loaded chitosan microspheres. The shell scaffolds were electrospun using collagen, polycaprolactone and hydroxyapatite materials to form CPH composite scaffolds with the ones containing ICA microspheres named CPHI. The core-shell scaffolds were then crosslinked by genipin. The morphology, microstructure, physical and mechanical properties of the scaffolds were assessed. Rat marrow mesenchymal stem cells from the wistar rat were cultured with the scaffolds. The cell adhesion and proliferation were analysed. Adult rabbit models with tibial plateau defects were used to evaluate the performance of these scaffolds in repairing the bone defects over 4 to 12 weeks. Results: The results reveal that the novel drug-loading core-shell scaffolds were successfully fabricated, which showed good physical and chemical properties and appropriate mechanical properties. Furthermore, excellent cells attachment was observed on the CPHI scaffolds. The results from radiography, micro-computed tomography, histological and immunohistochemical analysis demonstrated that abundant new bones were formed on the CPHI scaffolds. Conclusion: These new core-shell composite scaffolds have great potential for bone tissue engineering applications and may lead to effective bone regeneration and repair.
Toll-like receptor 4 (TLR4) families are receptors for ligands that initiate extracellular or intracellular signaling, such as lipopolysaccharides (LPS). It has been reported that TLR4 activation resulted in the upregulation of a coordinated set of proinflammatory mediators and inhibition of matrix expression in the intervertebral disc (IVD). miR-140-5p (miR-140) is reported to participate in cellular anti-inflammatory processes and target TLR4. In the present study, we investigated the relationship between TLR4 and miR-140 in IVD degeneration. The expression of TLR4, interleukin (IL)-6, IL-I, L-1β and tumor necrosis factor (TNF)-α was higher, in high-grade IVD degeneration tissues than in low-grade tissues. In contrast, the expression of miR-140, aggrecan and collagen type II was lower in high-grade IVD degeneration tissues than in low-grade IVD degeneration tissues. LPS stimulation resulted in significant increases in TLR4 expression and decreases in miR-140 expression in nucleus pulposus (NP) cells and TLR4 was identified as a target of miR-140 by dual-luciferase reporter assay. The overexpression of miR-140 inhibited the upregulation of the expression of TLR4, TNF-α, IL-1β and IL-6 inflammation cytokines, and the activation of NF-κB and reversed the downregulation of the expression of aggrecan and collagen type II induced by LPS stimulation. In conclusion, the present study may lead to a greater understanding of IVD degeneration and provide new insights into the treatment of this disease.
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