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Cell-cycle dependent nuclear gene delivery enhances the effects of E-cadherin against tumor invasion and metastasis

查看全文 作　　者：Liting [1]Xie;Jieqiong [2]Wang;Liming [3]Song;Tianan [1]Jiang;Fei [2]Yan 高影响力作者 机构地区：[1]Department of Ultrasound,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,310058,China;[2]CAS Key Laboratory of Quantitative Engineering Biology,Shenzhen Institute of Synthetic Biology,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,518055,China;[3]Department of Orthopedics,Zhujiang Hospital,Southern Medical University,Guangzhou,510280,China高影响力机构 出　　处：《Signal Transduction and Targeted Therapy》索引2023年第8卷第6期,共16页高影响力期刊 基　　金：supported by National Key R&D Program of China(Grant Number.2020YFA0908800);National Natural Science Foundation of China(Grant Number.81871376,32171365,82027803,81971623 and 82202151);Strategic Priority Research Program of the Chinese Academy of Sciences(Grant Number.XDB0480000);China Postdoctoral Science Foundation(Grant Number.2021M700121);Shenzhen Science and Technology Innovation Committee(Grant Number.JCYJ20190812171820731);Shenzhen Institute of Synthetic Biology Scientific Research Program(Grant Number.JCHZ20210002). 摘　　要：Gene delivery is the process by which foreign DNA is transferred to host cells,released from intracellular vesicles,and transported to the nuclei for transcription.This process is frequently inefficient and difficult to control spatiotemporally.We developed a gene delivery strategy that uses ultrasound to directly deliver plasmid DNA into nuclei via gas vesicles(GVs)-based intracellular cavitation.pDNA-binding GVs can be taken up by cells and cause intracellular cavitation when exposed to acoustic irradiation and delivering their pDNA payloads into nuclei.Importantly,GVs can remain stable in the cytoplasm in the absence of acoustic irradiation,allowing for temporally controlled nuclear gene delivery.We were able to achieve spatiotemporal control of E-cadherin nuclear gene delivery in this manner,demonstrating its efficacy in tumor invasion and metastasis inhibition.Interestingly,we discovered that nuclear gene delivery of E-cadherin during the G2/M phase of the cell cycle in C6 tumor cells inhibited tumor invasion and metastasis more effectively than during the G1 and S phases.The gene delivery of E-cadherin at the G2/M phase resulted in significantly lower expression of Fam50a,which reduced Fam50a/Runx2 interaction and led to reduced transactivation of MMP13,an important factor for epithelial-mesenchymal transition,as observed in a molecular mechanism assay.Thus,using remote acoustic control of intracellular cavitation of pDNA-GVs,we developed a high spatiotemporally controllable gene delivery strategy and achieved stronger tumor invasion and metastasis inhibition effects by delivering the E-cadherin gene at the G2/M phase. 关 键 词：INVASION METASTASIS inhibited
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