Purpose Glioblastoma (GBM), an extremely lethal and aggressive cancer with a poor prognosis and limited therapeutic outcomes, exhibits strong resistance to standard therapies owing to anoikis resistance indicating the need for novel treatments. In this study, we used thermoradiotherapy as an integrative approach for GBM to sensitize its resistance to anoikis. Experimental Design The therapeutic effects of thermoradiotherapy were assessed using cell counting kit-8, colony formation, Transwell, and anoikis assays. Proteomic analysis was performed to identify potential therapeutic targets for thermoradiotherapy. The impact of certain therapeutic target on GBM proliferation, metastasis, and anoikis was identified using EdU, colony formation, Transwell, and anoikis assays. Western blotting and qRT-PCR were used to explore the relevant molecular mechanisms. Results Thermoradiotherapy inhibited proliferation and metastasis of GBM, and reverses anoikis resistance to improve therapeutic outcomes. Proteomic analysis revealed ITGA5 as a prospective therapeutic target. In vitro and in vivo studies identified that ITGA5 promoted GBM proliferation, metastasis, and anoikis resistance by regulating PI3K/AKT pathway activation. Conclusions This study presents a novel thermoradiotherapy for GBM, integrating potent antitumour efficacy and negligible side effects. ITGA5 is a underlying therapeutic target for thermoradiotherapy which related to proliferation, metastasis, and anoikis resistance of GBM.
Jin Wu,Xiang Li,Hepeng Nie,Yue Shen,Zixiang Guo,Catherine Huihan Chu,Kunzhan Cai,Chunbo Tang
Diabetes-related hyperglycemia inhibits bone marrow mesenchymal stem cell (BMSC) function, thereby disrupting osteoblast capacity and bone regeneration. Dietary supplementation with phytic acid (PA), a natural inositol phosphate, has shown promise in preventing osteoporosis and diabetes-related complications. Emerging evidence has suggested that circular (circ)RNAs implicate in the regulation of bone diseases, but their specific regulatory roles in BMSC osteogenesis in hyperglycemic environments remain elucidated. In this study, in virto experiments demonstrated that PA treatment effectively improved the osteogenic capability of high glucose-mediated BMSCs. Differentially expressed circRNAs in PA-induced BMSCs were identified using circRNA microarray analysis. Here, our findings highlight an upregulation of circEIF4B expression in BMSCs stimulated with PA under a high-glucose microenvironment. Further investigations demonstrated that circEIF4B overexpression promoted high glucose-mediated BMSC osteogenesis . In contrast, circEIF4B knockdown exerted the opposite effect. Mechanistically, circEIF4B sequestered microRNA miR-186-5p and triggered osteogenesis enhancement in BMSCs by targeting FOXO1 directly. Furthermore, circEIF4B inhibited the ubiquitin-mediated degradation of IGF2BP3, thereby stabilizing ITGA5 mRNA and promoting BMSC osteogenic differentiation. In vivo experiments, circEIF4B inhibition attenuated the effectiveness of PA treatment in diabetic rats with cranial defects. Collectively, our study identifies PA as a novel positive regulator of BMSC osteogenic differentiation through the circEIF4B/miR-186-5p/FOXO1 and circEIF4B/IGF2BP3/ITGA5 axes, which offers a new strategy for treating high glucose-mediated BMSC osteogenic dysfunction and delayed bone regeneration in diabetes.
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