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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第12期24卷 1151-1158页

作者： Pengfei GAO Wentao ZHANG Yujie LIN Ruijie LU Zijian LOU Gang LU Ruolang PAN Yunfang CHEN Center for Plastic&Reconstructive Surgery Department of StomatologyZhejiang Provincial People's Hospital(Affiliated People's Hospital)Hangzhou Medical CollegeHangzhou 310014China School of Stomatology Bengbu Medical CollegeBengbu 233030China The Second Clinical Medical College Wenzhou Medical UniversityWenzhou 325035China Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province Hangzhou 31122China

Oral squamous cell carcinoma(OSCC)is a prevalent malignant tumor affecting the head and neck region(Leemans et al.,2018).It is often diagnosed at a later stage,leading to a poor prognosis(Muzaffar et al.,2021;Li et al.,2023).Despite advances in OSCC treatment,the overall 5-year survival rate of OSCC patients remains alarmingly low,falling below 50%(Jehn et al.,2019;Johnson et al.,2020).According to statistics,only 50%of patients with oral cancer can be treated with surgery.Once discovered,it is more frequently at an advanced stage.In addition,owing to the aggressively invasive and metastatic characteristics of OSCC,most patients die within one year of diagnosis.Hence,the pursuit of novel therapeutic drugs and treatments to improve the response of oral cancer to medication,along with a deeper understanding of their effects.

关键词： PLK1 metabolism drugs

The role of AFAP1-AS1 in mitotic catastrophe and metastasis of triple-negative breast cancer cells by activating the PLK1 signaling pathway

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Oncology Research 2023年第3期31卷 375-388页

作者： SHUIZHONG CEN XIAOJIE PENG JIANWEN DENG HAIYUN JIN ZHINAN DENG XIAOHUA LIN DI ZHU MING JIN YANWEN ZHU PUSHENG ZHANG YUNFENG LUO HONGYAN HUANG Department of Spinal Surgery Orthopedic Medical CenterZhujiang HospitalSouthern Medical UniversityGuangzhou510280China Department of Critical Care Medicine Nanfang HospitalSouthern Medical UniversityGuangzhou510515China Department of Breast Surgery Zhujiang HospitalSouthern Medical UniversityGuangzhou510280China Department of Gynecology and Obstetrics Southern Hospital Taihe BranchSouthern Medical UniversityGuangzhou510540China Department of Clinical Medicine Nanshan ClassGuangzhou Medical UniversityGuangzhou511436China Department of Gastroenterology Shenzhen HospitalSouthern Medical UniversityShenzhen518110China

Triple-negative breast cancer(TNBC)is characterized by fast growth,high metastasis,high invasion,and a lack of therapeutic targets.Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC malignant progression.It is well known that the long noncoding RNA AFAP1-AS1 plays a crucial role in various tumors,but whether AFAP1-AS1 is involved in the mitosis of TNBC cells remains unknown.In this study,we investigated the functional mechanism of AFAP1-AS1 in targeting Polo-like Kinase 1(PLK1)activation and participating in mitosis of TNBC cells.We detected the expression of AFAP1-AS1 in the TNBC patient cohort and primary cells by in situ hybridization(ISH),northern blot,fluorescent in situ hybridization(FISH)and cell nucleus/cytoplasm RNA fraction isolation.High AFAP1-AS1 expression was negatively correlated with overall survival(OS),disease-free survival(DFS),metastasis-free survival(MFS)and recurrence-free survival(RFS)in TNBC patients.We explored the function of AFAP1-AS1 by transwell,apoptosis,immunofluorescence(IF)and patient-derived xenograft(PDX)models in vitro and in vivo.We found that AFAP1-AS1 promoted TNBC primary cell survival by inhibiting mitotic catastrophe and increased TNBC primary cell growth,migration and invasion.Mechanistically,AFAP1-AS1 activated phosphorylation of the mitosis-associated kinase PLK1 protein.Elevated levels of AFAP1-AS1 in TNBC primary cells increased PLK1 pathway downstream gene expression,such as CDC25C,CDK1,BUB1 and TTK.More importantly,AFAP1-AS1 increased lung metastases in a mouse metastasis model.Taken together,AFAP1-AS1 functions as an oncogene that activates the PLK1 signaling pathway.AFAP1-AS1 could be used as a potential prognostic marker and therapeutic target for TNBC.

关键词： TNBC AFAP1-AS1 Mitotic catastrophe Metastasis PLK1

A zwitterionic polymer-inspired material mediated efficient CRISPR-Cas9 gene editing

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Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 666-678页

作者： Lingmin Zhang Langyu Yang Jionghua Huang Sheng Chen Chuangjia Huang Yinshan Lin Ao Shen ZhouYikang Zheng Wenfu Zheng Shunqing Tang Key Laboratory of Molecular Target&Clinical Pharmacology and the State&NMPA Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences&The Third and Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China Department of Biomedical Engineering Jinan UniversityGuangzhou 510632China CAS Key Lab for Biological Effects of Nanomaterials and Nanosafety National Center for NanoScience and TechnologyBeijing 100190China

The typeⅡ prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR/Cas9) adaptive immune system is a cutting-edge genome-editing toolbox.However,its applications are still limited by its inefficient transduction.Herein,we present a novel gene vector,the zwitterionic polymer-inspired material with branched structure (ZEBRA) for efficient CRISPR/Cas9 delivery.Polo-like kinase 1 (PLK1) acts as a master regulator of mitosis and overexpresses in multiple tumor cells.The Cas9 and single guide sgRNA (sgRNA)-encoded plasmid was transduced to knockout PLK1 gene,which was expected to inhibit the expression of PLK1.Our studies demonstrated that ZEBRA enabled to transduce the CRISPR/Cas9 system with large size into the cells efficiently.The transduction with ZEBRA was cell line dependent,which showed~10-fold higher in CD44-positive cancer cell lines compared with CD44-negative ones.Furthermore,ZEBRA induced highlevel expression of Cas9 proteins by the delivery of CRISPR/Cas9 and efficient gene editing of PLK1 gene,and inhibited the tumor cell growth significantly.This zwitterionic polymerinspired material is an effective and targeted gene delivery vector and further studies are required to explore its potential in gene delivery applications.

关键词： CRISPR/Cas9 Gene editing Zwitterionic polymers CD44 PLK1

探讨PLK1在卵母细胞减数分裂中的调控机制及其与有丝分裂的异同

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中华生殖与避孕杂志 2022年第3期42卷 318-323页

作者：姚波刘凤莫晓龙任艳萍遵义医科大学基础医学院组织胚胎学教研室遵义563000

Polo样激酶1(Polo-like kinase 1,PLK1)是丝氨酸/苏氨酸蛋白激酶家族成员之一。在有丝分裂中,PLK1参与控制中心体成熟、染色体凝聚、动粒-微管附着和胞质分裂。在哺乳动物卵母细胞减数分裂中PLK1也具有与在有丝分裂中类似的功能,但尚缺... 详细信息

Polo样激酶1(Polo-like kinase 1,PLK1)是丝氨酸/苏氨酸蛋白激酶家族成员之一。在有丝分裂中,PLK1参与控制中心体成熟、染色体凝聚、动粒-微管附着和胞质分裂。在哺乳动物卵母细胞减数分裂中PLK1也具有与在有丝分裂中类似的功能,但尚缺少PLK1在卵母细胞减数分裂调节机制方面的系统性的文献综述报道。本文从PLK1在卵母细胞减数分裂各时期的定位情况,及其在卵母细胞染色体凝聚、微管组织中心解聚、γ-微管蛋白和中心粒周蛋白的募集以及后期促进复合物/细胞周期体(anaphase-promoting complex/cyclostome,APC/C)的活化中的作用,这几个方面较为系统地探讨PLK1在卵母细胞减数分裂中的分子机制,及其在有丝分裂与减数分裂之间的异同,为进一步解析卵母细胞减数分裂的分子机制提供理论基础。

关键词： PLK1 卵母细胞减数分裂微管组织中心纺锤体形成

Ionizable lipid-assisted efficient hepatic delivery of gene editing elements for oncotherapy

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Bioactive Materials 2022年第3期7卷 590-601页

作者： Chunhui Li Tongren Yang Yuhua Weng Mengjie Zhang Deyao Zhao Shuai Guo Bo Hu Wanxuan Shao Xiaoxia Wang Abid Hussain Xing-Jie Liang Yuanyu Huang School of Life Science Advanced Research Institute of Multidisciplinary ScienceInstitute of Engineering MedicineKey Laboratory of Molecular Medicine and BiotherapyBeijing Institute of TechnologyBeijing100081China Department of Radiation Oncology The First Affiliated Hospital of Zhengzhou UniversityErqiZhengzhou450000China Institute of Molecular Medicine College of Future TechnologyPeking UniversityBeijing100871China Chinese Academy of Sciences(CAS)Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety CAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaBeijing100190China School of Materials and the Environment Beijing Institute of TechnologyZhuhai519085China

CRISPR/Cas9-based gene editing has emerged as a powerful biotechnological tool,that relies on Cas9 protein and single guided RNA(sgRNA)to edit target DNA.However,the lack of safe and efficient delivery carrier is one of the crucial factors restricting its clinical transformation.Here,we report an ionizable lipid nanoparticle(iLP181,pKa=6.43)based on iLY1809 lipid enabling robust gene editing in vitro and in vivo.The iLP181 effectively encapsulate psgPLK1,the best-performing plasmid expressing for both Cas9 protein and sgRNA targeting Polo-like kinase 1(PLK1).The iLP181/psgPLK1 nanoformulation showed uniformity in size,regular nanostructure and nearly neutral zeta potential at pH 7.4.The nanoformulation effectively triggered editing of PLK1 gene with more than 30%efficiency in HepG2-Luc cells.iLP181/psgPLK1 significantly accumulated in the tumor for more than 5 days after a single intravenous injection.In addition,it also achieved excellent tumor growth suppression compared to other nucleic acid modalities such as siRNA,without inducing adverse effects to the main organs including the liver and kidneys.This study not only provides a clinically-applicable lipid nanocarrier for delivering CRISPR/Cas system(even other bioactive molecules),but also constitutes a potential cancer treatment regimen base on DNA editing of oncogenes.

关键词： CRISPR/Cas Gene editing Lipid nanoparticle PLK1 Cancer therapy

以PLK1 PBD为靶点小分子抑制剂的筛选及抗肿瘤活性研究

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药学学报 2017年第3期52卷 409-415页

作者：姜玉环张晶陈云雨王艳宏司书毅黑龙江中医药大学黑龙江哈尔滨150000 中国医学科学院北京协和医学院医药生物技术研究所北京100050

采用荧光偏振高通量筛选的方法进行PLK1 PBD小分子抑制剂的筛选,对筛选出的阳性化合物F083-0063进行体外抗肿瘤活性研究,以期为寻找抗肿瘤药物提供先导化合物。模型筛选获取一个对PLK1 PBD抑制率较高的化合物F083-0063,其在10μg·mL^(... 详细信息

采用荧光偏振高通量筛选的方法进行PLK1 PBD小分子抑制剂的筛选,对筛选出的阳性化合物F083-0063进行体外抗肿瘤活性研究,以期为寻找抗肿瘤药物提供先导化合物。模型筛选获取一个对PLK1 PBD抑制率较高的化合物F083-0063,其在10μg·mL^(-1)时的抑制率达(99.7±0.4)%;利用软件Graphpad Prism 5计算IC_(50)为1.9±0.1μmol·L^(-1);噻唑蓝比色法(MTT)研究该化合物对不同细胞系增殖的影响,结果显示F083-0063能抑制多种肿瘤细胞系的增殖;流式细胞仪检测发现,其能促进细胞凋亡且能导致细胞G2/M期阻滞;划痕实验测定F083-0063对细胞迁移的影响,结果显示其能抑制He La细胞迁移,在20μmol·L^(-1)时,迁移率低至(37.6±0.7)%。利用分子连接技术探讨化合物与PLK1 PBD结构域的亲和力,发现F083-0063与PLK1 PBD有较好的亲和性;免疫印迹法(Western blotting)检测显示F083-0063可以引发周期相关蛋白表达的增加。综上所述,化合物F083-0063有明显的抗肿瘤活性,并有望成为靶向PLK1 PBD的抗肿瘤先导化合物。

关键词：抗肿瘤药荧光偏振法 PLK1 PBD抑制剂丝/苏氨酸蛋白激酶保罗样激酶

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中国人兽共患病学报 2023年第8期39卷 719-726页

作者：帕力塔吉·麦麦提祖农吴川川田梦潇齐文静艾柯代·卡得焦红杰龚巧巧李军张文宝张亚楼新疆医科大学基础医学院乌鲁木齐830017 新疆医科大学第一附属医院临床医学研究院中亚高发病成因与防治国家重点实验室乌鲁木齐830054

目的探究PLK1基因在细粒棘球绦虫不同发育时期的表达情况。方法体外培养细粒棘球绦虫原头蚴在犬胆汁刺激下向成虫方向发育,收集不同发育时期的虫体,通过免疫组化定位PLK1基因的表达。光学显微镜下切割分离成虫头节和后颈节段,收集样本... 详细信息

目的探究PLK1基因在细粒棘球绦虫不同发育时期的表达情况。方法体外培养细粒棘球绦虫原头蚴在犬胆汁刺激下向成虫方向发育,收集不同发育时期的虫体,通过免疫组化定位PLK1基因的表达。光学显微镜下切割分离成虫头节和后颈节段,收集样本运用荧光定量qPCR量化PLK1基因在虫体不同发育时期或不同部位的表达量水平,用SPSS 26.0软件进行单因素方差分析。结果成功建立了细粒棘球绦虫原头蚴向成虫方向发育的体外培养模型,体外培养的虫体56 d获得4个节片;PLK1基因在细粒棘球绦虫包囊生发层中高表达量。虽然在成虫和原头蚴表达较低,但免疫组化显示在原头蚴吸盘的底部和成虫头节的下部链体延长区域的表达高于其他部位(F=14.87,PPLK1的表达明显位于生发层细胞和激活原头蚴的头节底部以及链体增长区域,PLK1是棘球绦虫成虫发育干细胞区域的高表达基因。

关键词：细粒棘球绦虫体外培养 PLK1 免疫组化荧光定量PCR

miR-593通过调控PLK1基因的表达抑制结肠癌细胞的增殖

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南方医科大学学报 2019年第2期39卷 144-149页

作者：马金珠朱益平王箴昝嘉伟曹陇冯遵永王森林范倩颜亮皖南医学院活性生物大分子安徽省重点实验室安徽芜湖241002 皖南医学院第一附属医院安徽芜湖241022 安徽师范大学生命科学学院安徽芜湖241002 天津市肿瘤医院天津300060

目的探讨miR-593在结肠癌细胞增殖中的作用及分子机制。方法利用生物信息学分析筛选miR-593可能结合的靶基因为PLK1;利用双荧光素酶报告基因实验验证miR-593和PLK1基因的结合;通过qRT-PCR、Western blotting验证PLK1为miR-593直接作用... 详细信息

目的探讨miR-593在结肠癌细胞增殖中的作用及分子机制。方法利用生物信息学分析筛选miR-593可能结合的靶基因为PLK1;利用双荧光素酶报告基因实验验证miR-593和PLK1基因的结合;通过qRT-PCR、Western blotting验证PLK1为miR-593直接作用的靶基因;通过CCK-8实验证明miR-593通过调控PLK1基因的表达抑制结肠癌细胞的增殖。结果运用三种生物信息学软件对PLK1可能结合的miRNA进行了预测与分析,发现miR-593可能结合PLK1基因;双荧光素酶报告基因实验证明miR-593与PLK1基因发生了结合;Western blotting结果表明,PLK1在miR-593 mimic转染组表达量显著下降,而在miR-593 inhibitor组明显升高,相对于对照组均具有统计学差异(PPLK1 RNA水平在各组中表达水平差异无统计学意义(P>0.05);细胞增殖实验表明,miR-593与PLK1对结肠癌细胞增殖的影响为相反关系,且共转染miR-593mimic与PLK1过表达质粒组对细胞增殖的影响介于单独转染miR-593 mimic组与PLK1过表达质粒组之间。结论 miR-593通过调控PLK1基因的表达抑制了结肠癌细胞的增殖,并发挥抑癌miRNA的作用。

关键词： miR-593 结肠癌细胞 PLK1

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PLK1在套细胞淋巴瘤中的表达及临床意义

中国实验血液学杂志 2019年第3期27卷 833-838页

作者：沈绿瑛林聪猛福建医科大学附属漳州市医院血液内科

目的:研究PLK1在套细胞淋巴瘤中的表达,探讨shRNA干扰沉默PLK1基因表达对套细胞淋巴瘤Jeko-1细胞增殖、凋亡、周期的影响。方法:应用免疫组织化学S-P法检测42例套细胞淋巴瘤和30例反应性增生淋巴结炎患者组织中PLK1蛋白并进行分析与比较... 详细信息

目的:研究PLK1在套细胞淋巴瘤中的表达,探讨shRNA干扰沉默PLK1基因表达对套细胞淋巴瘤Jeko-1细胞增殖、凋亡、周期的影响。方法:应用免疫组织化学S-P法检测42例套细胞淋巴瘤和30例反应性增生淋巴结炎患者组织中PLK1蛋白并进行分析与比较。PLK1 shRNA慢病毒感染Jeko-1细胞,应用RQ-PCR检测PLK1 mRNA的表达及Western blot检测PLK1蛋白的表达,鉴定PLK1 shRNA干扰沉默效果,CCK-8试验检测细胞增殖,AnnexinⅤ/PI双染检测细胞凋亡, PI单染检测细胞周期,Western blot测定凋亡相关蛋白BAX BCL-2、Caspase-3的变化。结果:套细胞淋巴瘤患者组织中PLK1阳性率66.67%(28/42),明显高于增生淋巴结炎患者组织的20%(6/30)(P PLK1阳性表达与套细胞淋巴瘤患者B症状、IPI评分、Ann-Arbor临床分期存在相关性(P PLK1 shRNA慢病毒感染Jeko-1细胞72 h后,PLK1 mRNA和PLK1蛋白表达明显下降(PPLK1 shRNA组细胞增殖率明显低于对照和Neg shRNA组(P PLK1 shRNA组细胞的凋亡率为(27.42±3.44)%,明显高于对照组的(1.23±0.42)%和Neg shRNA组的(2.07±0.58)%(P PLK1 shRNA组的G2/M期细胞比例为(27.21±3.59)%,高于对照组的(13.28±2.63)%及Neg shRNA组的(14.34±2.37)%(P plkl在套细胞淋巴瘤患者组织中过量表达,干扰沉默PLK1基因可抑制人套细胞淋巴瘤Jeko-1细胞细胞增殖,诱导细胞凋亡,阻滞细胞周期于G2/M期。

关键词：套细胞淋巴瘤 PLK1 细胞凋亡细胞周期

PLK1在磷酰胺氮芥致卵巢颗粒细胞损伤中的作用及机制

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Plk1在磷酰胺氮芥致卵巢颗粒细胞损伤中的作用及机制

作者：黄欣怡湖南中医药大学

学位级别：硕士

目的:磷酰胺氮芥(Phosphoramidemustard,PM)损伤卵巢颗粒细胞(Granulosa cells,GCs)的分子机制具有复杂多样性,具体基因与作用信号通路尚不清楚。本课题基于RNA-seq技术和生物信息学研究PM损伤GCs的关键基因及潜在机制,并通过体外实验... 详细信息

目的:磷酰胺氮芥(Phosphoramidemustard,PM)损伤卵巢颗粒细胞(Granulosa cells,GCs)的分子机制具有复杂多样性,具体基因与作用信号通路尚不清楚。本课题基于RNA-seq技术和生物信息学研究PM损伤GCs的关键基因及潜在机制,并通过体外实验探究关键基因对细胞功能的调控和对下游信号通路的作用。方法:1.通过体外实验,以正常卵巢GCs作为对照,对PM损伤后GCs进行CCK8和流式细胞术评估细胞活性及细胞凋亡率;通过RNA-seq和生物信息学对测序数据进行分析,对差异基因采用GO、KEGG pathway富集分析,对基因集进行GSEA富集分析,构建PPI网络识别枢纽基因,以找到损伤机制之关键基因。2.在GCs中对关键基因丝氨酸/苏氨酸蛋白激酶PLK1(Polo-like Kinase 1,PLK1)进行过表达,将分组设为正常组(Control)、PM组(PM)、过表达空载组(OE-NC)、过表达空载+PM组(OE-NC+PM)、过表达PLK1组(OE-PLK1)、过表达PLK1+PM组(OE-PLK1+PM),通过CCK8、Ed U染色、流式细胞术检测凋亡及细胞周期,探讨过表达后GCs细胞功能改变。3.通过q RT-PCR和Western-blot检测Bax、Bcl-2、Caspase-3的mRNA及蛋白变化,Western-blot检测p-AKT表达水平。结果:1.测序结果表明正常组与PM组相比共有1261个差异表达基因,其中715个表达上调,546个表达下调。对差异基因进行GO功能富集分析(GO Enrichment Analysis,GO)富集,生物过程方面主要富集在染色体分离、核分裂、细胞器分裂等方面;细胞组分方面主要富集在浓缩染色体、染色体着丝粒区、染色体区域等方面;分子功能方面主要富集在催化活性、受体配体活性、催化活性,作用于DNA等。对差异基因进行京都基因与基因组百科全书KEGG(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集,下调基因包含DNA复制、细胞周期、白细胞介素-17信号通路等;上调基因包含MAPK信号通路、细胞色素P450对外源物质代谢的影响、化学致癌-受体激活通路等。基因集GSEA(Gene Set Enrichment Analysis,GSEA)富集结果包含细胞周期、白介素17信号通路、肿瘤坏死因子信号通路等。2.PM组与正常组相比、OE-NC+PM组与OE-NC组相比、OE-PLK1+PM组与OE-PLK1组相比细胞活性减弱、细胞增殖能力降低、细胞凋亡率增加、细胞周期紊乱(pPLK1+PM组与PM组及OE-NC+PM组相比,细胞活性增加、细胞增殖能力提高、细胞凋亡率减少、改善细胞周期紊乱(pPLK1+PM组与OE-PLK1组相比,Bax、Caspase-3 mRNA水平升高,Bax、Cleaved-Caspase-3蛋白水平升高、Bcl-2 mRNA及蛋白水平降低,p-AKT蛋白水平降低(pPLK1+PM组与PM组及OE-NC+PM组相比,Bax、Caspase-3 mRNA水平降低,Bax、Cleaved-Caspase-3蛋白水平降低,Bcl-2 mRNA及蛋白水平升高、p-AKT蛋白水平升高(p1.通过RNA-seq技术和生物信息学确定PM损伤GCs涉及多基因、多信号通路,其中PLK1为关键基因。2.过表达PLK1可抑制PM损伤GCs产生的细胞凋亡,促进细胞增殖。3.过表达PLK1通过激活AKT途径,上调Bcl-2、下调Bax及Caspase-3抑制PM导致的GCs细胞凋亡。

关键词： RNA-seq 生信分析卵巢颗粒细胞磷酰胺氮芥 PLK1