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Transcriptional regulatory network during axonal regeneration of dorsal root ganglion neurons:laser-capture microdissection and deep sequencing

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Neural Regeneration Research 2023年第9期18卷 2056-2066页

作者： Li-Li Zhao Tao Zhang Wei-Xiao Huang Ting-Ting Guo Xiao-Song Gu Model Animal Research Center and MOE Key Laboratory of Animal Models of Disease Nanjing UniversityNanjingJiangsu ProvinceChina Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina School of Medicine and Life Sciences Nanjing University of Chinese MedicineNanjingJiangsu ProvinceChina

The key regulators and regeneration-associated genes involved in axonal regeneration of neurons after injury have not been clarified.In high-throughput sequencing,various factors influence the final sequencing results,including the number and size of cells,the depth of sequencing,and the method of cell separation.There is still a lack of research on the detailed molecular expression profile during the regeneration of dorsal root ganglion neuron axon.In this study,we performed lase r-capture microdissection coupled with RNA sequencing on dorsal root ganglion neurons at 0,3,6,and 12 hours and 1,3,and 7 days after sciatic nerve crush in rats.We identified three stages after dorsal root ganglion injury:early(3-12 hours),pre-regeneration(1 day),and regeneration(3-7 days).Gene expression patterns and related function enrichment res ults showed that one module of genes was highly related to axonal regeneration.We verified the up-regulation of activating transcription factor 3(ATF3),Kruppel like factor 6(Klf6),AT-rich inte raction domain 5A(Arid5α),CAMP responsive element modulator(Crem),and FOS like 1,AP-1 transcription factor Subunit(Fosl1) in dorsal root ganglion neurons after injury.Suppressing these transcription factors(Crem,Arid5o,Fosl1 and Klf6) reduced axonal regrowth in vitro.As the hub transcription factor,ATF3 showed higher expression and activity at the preregeneration and regeneration stages.G protein-coupled estrogen receptor 1(Gper1),inte rleukin 12a(Il12α),estrogen receptor 1(ESR1),and interleukin 6(IL6) may be upstream factors that trigger the activation of ATF3 during the repair of axon injury in the early stage.Our study presents the detailed molecular expression profile during axonal regeneration of dorsal root ganglion neurons after peripheral nerve injury.These findings may provide reference for the clinical screening of molecular targets for the treatment of peripheral nerve injury.

关键词： Arid5a ATF3 Crem dorsal root ganglion Fosl1 Klf6 laser-capture microdissection neuron smart-seq2 gene expression profile transcription factor

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3085-3102页

作者： Ningna Weng Siyuan Qin Jiayang Liu Xing Huang Jingwen Jiang Li Zhou Zhe Zhang Na Xie Kui Wang Ping Jin Maochao Luo Liyuan Peng Edouard C.Nice Ajay Goel Suxia Han Canhua Huang Qing Zhu Department of Abdominal Oncology West China Hospital of Sichuan UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityCollaborative Innovation Center for BiotherapyChengdu 610041China Department of Pancreatic Surgery West China Hospital of Sichuan UniversityChengdu 610041China Department of Biochemistry and Molecular Biology Monash UniversityClaytonVIC 3800Australia Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of HopeBiomedical Research CenterMonroviaCA 91016USA Department of Oncology the First Affiliated HospitalXi’an Jiaotong UniversityXi’an 710061China

Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.However,current realization is impeded by its suboptimal use and unpredictable toxicity.Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach.Here,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top candidate.Further testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional autophagy.More specifically,ECON boosted autophagy initiation but blocked lysosome biogenesis.RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC cells.The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis.Furthermore,ECON,as an autophagy inhibitor,exhibited synergistic effects with trametinib on PDAC.This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

关键词： Econazole Autophagy PDAC ATF3 AKT Organoid Trametinib Therapy

Sphingosine kinase 1 promotes growth of glioblastoma by increasing inflammation mediated by the NF-κB/IL-6/STAT3 and JNK/PTX3 pathways

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4390-4406页

作者： Wan Li Hongqing Cai Liwen Ren Yihui Yang Hong Yang Jinyi Liu Sha Li Yizhi Zhang Xiangjin Zheng Wei Tan Guanhua Du Jinhua Wang The State Key Laboratory of Bioactive Substance and Function of Natural Medicines Beijing 100050China Key Laboratory of Drug Target Research and Drug Screen Institute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100050China Department of Neurosurgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology Center for Cancer Precision MedicineNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China School of Pharmacy Xinjiang Medical UniversityUrumqi 830011China Xinjiang Institute of Materia Medica Urumqi 830004China

Glioblastoma(GBM)is the most challenging malignant tumor of the central nervous system because of its high morbidity,mortality,and recurrence rate.Currently,mechanisms of GBM are still unclear and there is no effective drug for GBM in the clinic.Therefore,it is urgent to identify new drug targets and corresponding drugs for GBM.In this study,in silico analyses and experimental data show that sphingosine kinase 1(SPHK1)is up-regulated in GBM patients,and is strongly correlated with poor prognosis and reduced overall survival.Overexpression of SPHK1 promoted the proliferation,invasion,metastasis,and clonogenicity of GBM cells,while silencing SPHK1 had the opposite effect.SPHK1 promoted inflammation through the NF-κB/IL-6/STAT3 signaling pathway and led to the phosphorylation of JNK,activating the JNK-JUN and JNK-ATF3 pathways and promoting inflammation and proliferation of GBM cells by transcriptional activation of PTX3.SPHK1 interacted with PTX3 and formed a positive feedback loop to reciprocally increase expression,promote inflammation and GBM growth.Inhibition of SPHK1 by the inhibitor,PF543,also decreased tumorigenesis in the U87-MG and U251-MG SPHK1 orthotopic mouse models.In summary,we have characterized the role and molecular mechanisms by which SPHK1 promotes GBM,which may provide opportunities for SPHK1-targeted therapy.

关键词： Glioblastoma Drug target SPHK1 Inflammation NF-κB/IL-6/STAT3 signal pathway ATF3 PXT3

通关藤注射液通过调控ATF3表达对紫杉醇抗乳腺癌细胞的增效作用

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中成药 2022年第6期44卷 1774-1782页

作者：张葳陈君君杨姣石美智姜波周丽孔欠文韩永龙上海海洋大学食品学院上海201306 上海交通大学附属第六人民医院药剂科上海200233

目的探讨ATF3介导的通关藤注射液增强紫杉醇抗乳腺癌的作用机制。方法体外培养人乳腺癌MDA-MB-231细胞,siRNA干扰ATF3的表达,给予通关藤注射液和紫杉醇单独或联合干预。采用RT-qPCR和Western blot法分别检测ATF3及相关细胞因子CCL2、T... 详细信息

目的探讨ATF3介导的通关藤注射液增强紫杉醇抗乳腺癌的作用机制。方法体外培养人乳腺癌MDA-MB-231细胞,siRNA干扰ATF3的表达,给予通关藤注射液和紫杉醇单独或联合干预。采用RT-qPCR和Western blot法分别检测ATF3及相关细胞因子CCL2、TNF-α的表达,细胞划痕实验和Transwell实验检测细胞迁移和侵袭能力,Hoechst活细胞染色和流式细胞术检测细胞凋亡情况。结果在ATF3-siRNA干扰的MDA-MB-231细胞中,紫杉醇可上调ATF3 mRNA和蛋白表达及细胞因子CCL2、TNF-α mRNA表达(PATF3 mRNA和蛋白表达升高的趋势,可抵消细胞因子CCL2、TNF-α mRNA表达的上调(P31细胞的增殖和转移、诱导细胞凋亡,并且联合紫杉醇组的作用更为显著(PATF3及相关细胞因子的表达,抑制乳腺癌细胞的增殖、转移、侵袭,促进乳腺癌细胞的凋亡,从而发挥增效作用。

关键词：通关藤注射液乳腺癌 MDA-MB-231细胞紫杉醇 ATF3 CCL2 TNF-α

Echinacoside Protects Against MPP+-Induced Neuronal Apoptosis via ROS/ATF3/CHOP Pathway Regulation

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Neuroscience Bulletin 2016年第4期32卷 349-362页

作者： Qing Zhao Xiaoyan Yang Dingfang Cai Ling Ye Yuqing Hou Lijun Zhang Jiwei Cheng Yuan Shen Kaizhe Wang Yu Bai Department of Neurology Putuo HospitalShanghai University of Traditional Chinese Medicine Department of Emergency Internal Medicine Putuo HospitalShanghai University of Traditional Chinese Medicine Laboratory of Neurology Institute of Integrative MedicineZhongshan Hospital Fudan University Department of Integrative Medicine Zhongshan HospitalFudan University Center for Translational Neurodegeneration and Regenerative Therapy Shanghai Tenth People’s Hospital Affiliated with Tongji University School of Medicine Department of Immunology Tongji University School of Medicine

Echinacoside （ECH） is protective in a mouse model of Parkinson＇ s disease （PD） induced by 1-methyl-4- phenylpyridinium ion （MPP＋）. To investigate the mechanisms involved, SH-SYSY neuroblastoma ceils were treated with MPP＋ or a combination of MPP＋ and ECH, and the expression of ATF3 （activating transcription factor 3）, CHOP （C/EBP-homologous protein）, SCNA （synuclein alpha）, and GDNF （glial cell line-derived neurotrophic factor） was assessed. The results showed that ECH significantly improved cell survival by inhibiting the generation of MPP＋-induced reactive oxygen species （ROS）. In addition, ECH suppressed the ROS and MPP＋- induced expression of apoptotic genes （ATF3, CHOP, and SCNA）. ECH markedly decreased the MPP＋-induced cas- pase-3 activity in a dose-dependent manner. ATF3- knockdown also decreased the CHOP and cleaved caspase- 3 levels and inhibited the apoptosis induced by MPP＋. Interestingly, ECH partially restored the GDNF expression that was down-regulated by MPP＋. ECH also improved dopaminergic neuron survival during MPP＋ treatment and protected these neurons against the apoptosis induced by MPTP. Taken together, these data suggest that the ROS/ ATF3/CHOP pathway plays a critical role in mechanisms by which ECH protects against MPP＋-induced apoptosis in PD.

关键词： Echinacoside Parkinson＇s disease 1-Methyl-4-phenylpyridinium ion. Reactive oxygen species ATF3 CHOP

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ATF3对乳腺癌的作用研究进展

中国药理学通报 2020年第6期36卷 750-753页

作者：张葳陈君君杨姣石美智韩永龙上海海洋大学食品学院上海201306 上海健康医学院附属第六人民医院东院药剂科上海201306 上海交通大学附属第六人民医院药剂科上海200233

转录激活因子3(activating transcription factor 3,ATF3)作为转录激活因子,可通过调控细胞增殖及凋亡机制的平衡在乳腺癌的形成、转移和治疗中发挥着重要作用,而乳腺癌作为女性最常见的恶性肿瘤一直是医学界广泛关注的热点。该文就atf... 详细信息

转录激活因子3(activating transcription factor 3,ATF3)作为转录激活因子,可通过调控细胞增殖及凋亡机制的平衡在乳腺癌的形成、转移和治疗中发挥着重要作用,而乳腺癌作为女性最常见的恶性肿瘤一直是医学界广泛关注的热点。该文就ATF3在乳腺癌中调节增殖、侵袭和转移机制,化、放疗敏感性以及相关信号通路调节方面的研究进展进行介绍,阐述ATF3与乳腺癌之间的关系,为乳腺癌的临床治疗提供参考靶点和理论依据。

关键词：乳腺癌 ATF3 侵袭转移化疗敏感性放疗敏感性信号通路调节

糖尿病肾病患者血清ATF3与蛋白尿的相关性分析

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糖尿病肾病患者血清ATF3与蛋白尿的相关性分析

作者：王小霞山西医科大学

学位级别：硕士

目的:探讨糖尿病肾病(Diabetic kidney disease,DKD)患者血清关键基因转录激活因子3(Activating transcription factor 3,ATF3)水平变化及其与蛋白尿的相关性,为进一步寻找早期识别DKD的生物标志物提供理论依据。方法:首先在GEO数据库... 详细信息

目的:探讨糖尿病肾病(Diabetic kidney disease,DKD)患者血清关键基因转录激活因子3(Activating transcription factor 3,ATF3)水平变化及其与蛋白尿的相关性,为进一步寻找早期识别DKD的生物标志物提供理论依据。方法:首先在GEO数据库中根据纳入排除标准选择合适的基因数据集,之后对其进行差异基因和加权基因共表达网络分析(WGCNA),最后将二者结果取交集获得DKD相关基因。将其导入Cytoscape软件,根据Degree算法,进行筛选获得排名靠前的5个关键基因。之后选取2020年12月-2021年11月在我院肾内科门诊或住院部明确诊断为DKD患者,根据纳入及排除标准,筛选符合条件的DKD患者。测定其随机尿白蛋白/肌酐(UACR),根据测定的UACR值将最终纳入的病例分为:正常白蛋白尿组(UACR30mg/g)、微量白蛋白尿组(UACR:30-300mg/g)、大量白蛋白尿组(UACR>300mg/g)。收集其一般资料及生化指标,运用酶联免疫吸附法(ELISA)对患者血清ATF3浓度进行测定;三组间一般资料及各项临床指标差异采用方差分析或非参数检验进行比较;血清ATF3与各项临床指标的相关性采用Pearson或Spearman进行分析;采用多重线性逐步回归法对血清ATF3的影响因素进行分析。结果:1.选择GSE142153数据集作为研究,进行差异基因及WGCNA分析并取交集后,共获得48个DKD相关基因,进一步筛选后获得前5个关键基因,分别为IL10、IL1A、ATF3、CCL2、CXCR3。2.最终纳入88例DKD患者,正常白蛋白尿组26例,微量白蛋白尿组30例,大量白蛋白尿组32例。三组患者间年龄、性别比、BMI均未见明显差异。与正常白蛋白尿组相比,微量白蛋白尿组与大量白蛋白尿组Hb、ALB显著降低(P3.与正常白蛋白尿组相比,其他两组血清ATF3浓度明显升高,大量白蛋白尿组血清ATF3浓度最高,差异具有统计学意义(PATF3浓度与各临床指标及蛋白尿进行相关性分析后发现,血清ATF3浓度与Hb、ALB、GFR呈负相关(r=-0.525,-0.751,-0.406,P均ATF3浓度进一步行多重线性逐步回归分析后发现,Hb、UACR、24小时尿蛋白定量均为ATF3的影响因素,且24小时尿蛋白定量对其影响较大。结论:DKD患者血清ATF3水平明显升高,与蛋白尿的严重程度存在正相关,有望成为监测DKD的临床指标。

关键词：生物信息学 WGCNA 糖尿病肾病 ATF3 蛋白尿

Lipofermata通过FATP2-ATF3轴调控PI3K/Akt/mTOR信号通路抑制膀胱癌发生发展的作用与机制研究

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Lipofermata通过FATP2-ATF3轴调控PI3K/Akt/mTOR信号通路抑制膀胱...

作者：江明南昌大学

学位级别：硕士

研究背景及目的:至2020年,全球已有786,000人因膀胱癌去世且新增死亡病例占总死亡病例的70%以上。在我国男性患者中,膀胱癌新发病例为7万,排名第8位,其病例数逐年增加,已然成为危害我国居民健康的重要疾病。根据“种子与土壤”假说,肿... 详细信息

研究背景及目的:至2020年,全球已有786,000人因膀胱癌去世且新增死亡病例占总死亡病例的70%以上。在我国男性患者中,膀胱癌新发病例为7万,排名第8位,其病例数逐年增加,已然成为危害我国居民健康的重要疾病。根据“种子与土壤”假说,肿瘤生长的最佳环境是一种能够增强癌细胞增殖能力并抑制其死亡的环境。这种环境在体内由肿瘤微环境(Tumor microenvironment,TME)提供,在肿瘤转移及对药物的耐受中发挥重要作用。在与脂肪高度相关的卵巢癌及乳腺癌等肿瘤的研究中,经脂肪细胞提供的脂质被认为是肿瘤代谢生长的能量来源。脂肪酸转运蛋白家族(Fat acid transport proteins,FATPs)主要在脂质代谢旺盛及摄取脂肪酸活跃的组织表达,内毒素、TNFα等炎症因子及胰岛素之类的激素都能调节FATPs成员的表达。FATPs被报道在哺乳动物中过表达时会增加脂肪酸的摄取,而脂质代谢的失调往往与肿瘤的发生发展有关。FATP2主要在肝脏、肾脏和肠道中表达,在调节外源性脂肪酸运输和维持细胞内脂质平衡方面起着重要作用。有研究表明脂肪酸转运蛋白2抑制剂(Lipofermata)可以增强免疫抑制剂的疗效并通过抑制FATP2抑制多形核骨髓源性抑制细胞(Polymorphonuclear-Myeloid derived srppressor cells,PMN-MDSCs)的促癌作用。多项研究结果表明FATP2在肿瘤治疗方面有着很大的潜力,而Lipofermata作为FATP2的抑制剂,在PMN-MDSCs和黑色素瘤中的研究中已经显示了一定的抗肿瘤作用。在本研究中,我们将深入探究Lipofermata对膀胱癌细胞增殖、迁移等细胞生物学影响以及Lipofermata如何通过调控FATP2-ATF3轴影响膀胱癌细胞的增殖和EMT,探讨Lipofermata作为膀胱癌新型治疗药物的可行性。研究方法:实时荧光定量(Real time quantitative PCR,RT-q PCR)及蛋白质印记(Western blot,WB)用于检测m RNA及蛋白的相对表达量。免疫组化(Immunohistochemistry,IHC)及免疫荧光(Immunofluorescence,IF)实验用于检测蛋白在细胞中的定位并检测其表达。CCK-8(Cell Counting Kit-8)、细胞平板克隆实验、伤口愈合实验、Transwell及流式细胞术用来检测T24、J82两株肌层浸润型膀胱癌细胞增殖、迁移、侵袭等能力。裸鼠皮下成瘤实验研究Lipofermata在体内实验中对膀胱癌肿瘤的影响及药物本身的毒副作用。有参转录组测序检测药物作用后细胞的分子及通路变化。研究结果:RT-q PCR、IHC及WB结果表明FATP2在大部分膀胱癌细胞及组织中表达升高,CCK-8法、细胞平板克隆实验、伤口愈合实验、Transwell实验等细胞功能实验表明敲减SLC27A2能抑制膀胱癌细胞的增殖、迁移能力。细胞半数抑制浓度(IC50)结果显示膀胱癌细胞对Lipofermata敏感性与FATP2的表达正相关。各种细胞实验表明Lipofermata能诱导膀胱癌细胞的凋亡而阻滞周期并抑制其侵袭、迁移及增殖。裸鼠成瘤实验表明Lipofermata在体内依然能发挥抗膀胱癌作用且无明显毒副作用。测序及细胞回复实验表明Lipofermata是通过FATP2-ATF3轴抑制膀胱癌EMT并通过调控PI3K/Akt/m TOR信号通路抑制膀胱癌增殖。研究结论:1.FATP2在人膀胱癌细胞及组织中表达升高且高表达患者预后更差,其存在促进细胞增殖及迁移,是膀胱癌治疗的潜在分子靶点。2.FATP2抑制剂Lipofermata能通过下调FATP2的表达从而抑制膀胱癌细胞的增殖、EMT并阻滞周期诱导细胞凋亡,其在裸鼠体内亦能发挥抗肿瘤作用且对体重无明显影响。3.Lipofermata通过FATP2-ATF3轴发挥抗膀胱肿瘤能力与PI3K/Akt/m TOR信号通路高度相关。

关键词： Lipofermata FATP2 ATF3 PI3K/Akt/mTOR EMT 膀胱癌

Effect of ATF3-deletion on apoptosis of cultured retinal ganglion cells

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International Journal of Ophthalmology(English edition) 2017年第5期10卷 691-695页

作者： Ming-Ming Sun Ya-Chen Wang Yi Li Xiao-Dan Guo Yan-Ming Chen Zhong-Zhi Zhang Ophthalmology Department the First Hospital of China Medical University Shenyang 110001 Liaoning ProvinceChina

AIM：To investigate the effect of activating transcription factor-3（ATF3）-deletion on apoptosis of cultured retinal ganglion cells（RGCs）.METHODS：Three ATF3 siR NA（ATF3-rat-651, ATF3-rat-319, ATF3-rat-520） were constructed, and were transiently transfected into RGC-5 cells. Quantitative real-time polymerase chain reaction（PCR） was used to examine ATF3 expression and the most effective ATF3 siR NA was selected for further studies. Flow cytometry was applied to investigate the effects of ATF3 deletion on RGC-5 apoptosis under elevated hydrostatic pressure. Quantitative realtime PCR and Western blot were performed to validate differentially expressed genes and proteins in ATF3-knockdown RGC-5 cells.RESULTS：ATF3 specific siR NA effectively down-regulated ATF3 expression and significantly inhibited cell apoptosis in RGC-5 cells. Quantitative real-time PCR and Western blot confirmed that ATF3 knockdown remarkably decreased Jun-B and increased c-Jun at both m RNA and protein levels in RGC-5 cells.CONCLUSION：atf/cA MP-response element-binding family of transcription factors may be involved in the development of glaucoma and could be novel treatment targets for glaucoma.

关键词： ATF3 elevated hydrostatic pressure apoptosis glaucoma