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Zinc oxide nanoparticles inhibit osteosarcoma metastasis by downregulatingβ-catenin via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway

查看全文 作　　者：Guanping [1,3]He;Jing-Jun [2]Nie;Xiao [3]Liu;Zihao [1]Ding;Peng [2]Luo;Yu [3]Liu;Bo-Wen [2]Zhang;Renxian [2]Wang;Xiaoguang [3]Liu;Yong [1]Hai;Da-Fu [2]Chen 高影响力作者 机构地区：[1]Department of Orthopedics,Beijing Chao-Yang Hospital,Capital Medical University,Beijing,100020,China;[2]Laboratory of Bone Tissue Engineering,Beijing Laboratory of Biomedical Materials,Beijing Research Institute of Traumatology and Orthopaedics,Beijing Jishuitan Hospital,Beijing,100035,China;[3]Department of Orthopedics,Peking University Third Hospital,Beijing,100191,China高影响力机构 出　　处：《Bioactive Materials》索引2023年第1期,共13页高影响力期刊 基　　金：supported in part by Beijing Natural Science Foundation(7192226,7222011);Beijing Chao-Yang Hospital Golden Seeds Foundation(CYJZ202148);National Key Research and Development Program(2021YFC2400500);National Natural Science Foundation of China(51903013,51973021,51932002,52173275);Beijing Hospitals Authority Youth Programme(QML20210402);the Beijing Municipal Health Commission(PXM 2020_026275_000002,BMHC-2021-6,BMHC-2019-9). 摘　　要：Osteosarcoma(OS)therapy faces many challenges,especially the poor survival rate once metastasis occurs.Therefore,it is crucial to explore new OS treatment strategies that can efficiently inhibit OS metastasis.Bioactive nanoparticles such as zinc oxide nanoparticles(ZnO NPs)can efficiently inhibit OS growth,however,the effect and mechanisms of them on tumor metastasis are still not clear.In this study,we firstly prepared well-dispersed ZnO NPs and proved that ZnO NPs can inhibit OS metastasis-related malignant behaviors including migration,invasion,and epithelial-mesenchymal transition(EMT).RNA-Seqs found that differentially expressed genes(DEGs)in ZnO NP-treated OS cells were enriched in wingless/integrated(Wnt)and hypoxia-inducible factor-1(HIF-1)signaling pathway.We further proved that Zn^(2+)released from ZnO NPs induced downregulation ofβ-catenin expression via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway.ZnO NPs combined with ICG-001,aβ-catenin inhibitor,showed a synergistic inhibitory effect on OS lung metastasis and a longer survival time.In addition,tissue microarray(TMA)of OS patients also detected much higherβ-catenin expression which indicated the role ofβ-catenin in OS development.In summary,our current study not only proved that ZnO NPs can inhibit OS metastasis by degradingβ-catenin in HIF-1α/BNIP3/LC3B-mediated mitophagy pathway,but also provided a far-reaching potential of ZnO NPs in clinical OS treatment with metastasis. 关 键 词：Zinc oxide nanoparticle HIF-1α/BNIP3/LC3B-mediated mitophagy PATHWAY METASTASIS OSTEOSARCOMA
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