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转录因子atf3与前列腺癌临床相关性的分析研究

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安徽医专学报 2024年第2期23卷 90-93页

作者：徐凌凡丁和康施浩强杨诚邰胜安徽医科大学第一附属医院泌尿外科安徽合肥230022

目的:探究转录因子atf3与前列腺癌的临床相关性,了解atf3在前列腺癌组织中的表达以及其表达强度对前列腺癌患者预后的影响。方法:采用公共数据库挖掘的方法分析atf3在前列腺癌组织中的突变情况以及atf3在正常前列腺组织以及前列腺癌组... 详细信息

目的:探究转录因子atf3与前列腺癌的临床相关性,了解atf3在前列腺癌组织中的表达以及其表达强度对前列腺癌患者预后的影响。方法:采用公共数据库挖掘的方法分析atf3在前列腺癌组织中的突变情况以及atf3在正常前列腺组织以及前列腺癌组织中的表达情况,kaplan-meier方法分析atf3的表达强度与前列腺癌患者临床预后的相关性;免疫组化染色验证atf3在正常前列腺组织和前列腺癌组织中的蛋白表达;患者临床信息分析atf3的表达高低与前列腺癌临床特征的关联。结果:atf3在前列腺癌组织中表现为高扩增突变,且atf3在前列腺癌组织中的表达明显高于正常前列腺组织;atf3与前列腺癌疾病的发生、进展(病灶转移)相关;高表达atf3的前列腺癌患者预后较差。结论:atf3的表达强度与前列腺癌的发生发展相关,可作为前列腺癌诊断及预后判断的重要指标。

关键词：前列腺癌 atf3 免疫组化前列腺特异性抗原

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

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

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

过表达山羊atf3抑制肌内前体脂肪细胞分化

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生物工程学报 2022年第8期38卷 2939-2947页

作者：王重洋罗成张浩李鑫李艳艳熊燕王友利林亚秋西南民族大学畜牧兽医学院四川成都610041 西南民族大学青藏高原动物遗传资源保护与利用教育部/四川省重点实验室四川成都610041

本研究旨在探究山羊转录激活因子3(activating transcription factor 3,atf3)对肌内前体脂肪细胞分化的影响,并从分子水平阐明其可能作用途径。利用基因重组方法构建pEGFP-N1-atf3过表达重组质粒,脂质体转染肌内前体脂肪细胞,通过油红O... 详细信息

本研究旨在探究山羊转录激活因子3(activating transcription factor 3,atf3)对肌内前体脂肪细胞分化的影响,并从分子水平阐明其可能作用途径。利用基因重组方法构建pEGFP-N1-atf3过表达重组质粒,脂质体转染肌内前体脂肪细胞,通过油红O脂肪染色法从细胞形态学水平确定对分化的影响,利用实时荧光定量PCR(qRT-PCR)技术检测脂肪细胞分化标记基因相对表达水平,从分子水平确定对分化的影响。最终成功构建pEGFP-N1-atf3过表达载体,转染山羊肌内前体脂肪细胞后发现脂滴积聚被抑制,qRT-PCR检测到脂肪细胞分化标志基因PPARγ、C/EBPα、SREBP1极显著下调(Patf3结合位点。研究表明,过表达山羊atf3抑制肌内前体脂肪细胞脂滴积聚,这种作用通过下调PPARγ、C/EBPα和AP2来实现,研究结果为阐明山羊atf3调控肌内前体脂肪细胞分化机制提供重要的基础数据。

关键词： atf3 山羊肌内前体脂肪细胞过表达诱导分化

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

Activating transcription factor 3,glucolipid metabolism,and metabolic diseases

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Journal of Molecular Cell Biology 2022年第10期14卷 1-10页

作者： Shuwei Hu Xiaojie Zhao Rui Li Chencheng Hu Huĳuan Wu Jing Li Yanqiao Zhang Yanyong Xu Department of Integrative Medical Sciences Northeast Ohio Medical UniversityRootstownOH 44272USA Department of Pathology School of Basic Medical SciencesFudan UniversityShanghai 200032China Department of Endocrinology Beĳing Chao-yang HospitalCapital Medical UniversityBeĳing 100020China Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education Department of Pathology of School of Basic Medical SciencesFudan UniversityShanghai 200032China Frontier Innovation Center School of Basic Medical SciencesFudan UniversityShanghai 200032China

Lipids and glucose exert many essential physiological functions,such as providing raw materials or energy for cellular biosynthesis,regulating cell signal transduction,and maintaining a constant body temperature.Dysregulation of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases,such as obesity,diabetes,and cardiovascular disease.Therefore,intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic diseases.Activating transcription factor 3(atf3)is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation,apoptosis,DNA repair,and oncogenesis.Emerging evidence has illustrated the vital roles of atf3 in glucolipid metabolism.atf3 inhibits intestinal lipid absorption,enhances hepatic triglyceride hydrolysis and fatty acid oxidation,promotes macrophage reverse cholesterol transport,and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and atherosclerosis.In addition to its role in lipid metabolism,atf3 has also been identified as an important regulator of glucose metabolism.Here,we summarize the recent advances in the understanding of atf3,mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.

关键词： atf3 glucolipid metabolism metabolic organ metabolic diseases

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

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