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usp51/PD-L1/ITGB1-deployed juxtacrine interaction plays a cell-intrinsic role in promoting chemoresistant phenotypes in non-small cell lung cancer

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Cancer Communications 2023年第7期43卷 765-787页

作者： Jianjun Li Xuechun Xiao Yang Ou Lixia Cao Min Guo Chunchun Qi Zhaoyang Wang Yuxin Liu Qiuying Shuai Hang Wang Peiqing Sun Yi Shi Guang Yang Shuang Yang Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation School of MedicineNankai UniversityTianjinP.R.China Department of Pulmonary and Critical Care Medicine The First Affiliated Hospital of Soochow UniversitySuzhouJiangsuP.R.China Department of Cancer Biology Wake Forest University School of MedicineWinston-SalemNCUSA College of Pharmacy Nankai UniversityTianjinP.R.China Institute of Transplantation Medicine Nankai UniversityTianjinP.R.China

Background:Programmed death ligand 1(PD-L1)has been demonstrated to facilitate tumor progression and therapeutic resistance in an immuneindependent ***,the function and underlying signaling network(s)of cancer cell-intrinsic PD-L1 action remain largely ***,we sought to better understand how ubiquitin-specific peptidase 51(usp51)/PD-L1/integrin beta-1(ITGB1)signaling performs a cell-intrinsic role in mediating chemotherapeutic resistance in non-small cell lung cancer(NSCLC).Methods:Western blotting and flow cytometry were employed for PD-L1 detection in NSCLC cell *** and pulldown analyses,protein deubiquitination assay,tissue microarray,bioinformatic analysis and molecular biology methods were then used to determine the significance of PD-L1 in NSCLC chemoresistance and associated signaling pathways in several different cell lines,mouse models and patient tissue ***-7-amido-4-methylcoumarin(Ub-AMC)-based deubiquitinase activity,cellular thermal shift and surface plasmon resonance(SPR)analyses were performed to investigate the activity of usp51 ***:We provided evidence that cancer cell-intrinsic PD-L1 conferred the development of chemoresistance by directly binding to its membrane-bound receptor ITGB1 in *** the molecular level,PD-L1/ITGB1 interaction subsequently activated the nuclear factor-kappa B(NF-κB)axis to elicit poor response to *** further determined usp51 as a bona fide deubiquitinase that targeted the deubiquitination and stabilization of the PD-L1 protein in chemoresistant NSCLC ***,we found a significant direct relationship between the usp51,PD-L1 and ITGB1 contents in NSCLC patients with chemoresistant *** elevated usp51,PD-L1 and ITGB1 levels were strongly associated with worse patient *** note,we identified that a flavonoid compound dihydromyricetin(DHM)acted as a potential usp51 inhibitor and rendered NSCLC cells more sensit

关键词： chemosensitivity dihydromyricetin immune-independence ITGB1 non-small cell lung cancer PD-L1 usp51

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usp51 confers chemoresistance by triggering PD-L1/ITGB1 signaling in NSCLC

USP51 confers chemoresistance by triggering PD-L1/ITGB1 sign...

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第十四届全国免疫学学术大会

作者： Jianjun Li Xuechun Xiao hang Wang Shuang Yang School of Medicine Nankai University

Chemoresistance is a major obstacle to the successful treatment of non-small-cell lung cancer(NSCLC).Although PDL1 has been shown to play a pivotal role in inhibiting antitumor immunity via engagement of the PD-1 receptor on T lymphocytes,little is known about the tumor cell-intrinsic function of PD-L1 in human ***,we dissect the underlying mechanisms of aberrant PD-L1 in the development of chemoresistance in *** results showed that PDL1 significantly reduces chemotherapy-mediated killing through a cell-intrinsic mechanism in NSCLC both in vitro and in *** the molecular level,the extracellular domain of PD-L1 directly interacts with its membrane-bound receptor ITGB1 that subsequently activates the NF-κB signaling pathway to promote the chemotherapeutic resistance in NSCLC *** note,we identified usp51 as a bona fide deubiquitinase that targets the PD-L1 protein for deubiquitination and stabilization in chemoresistant NSCLC ***,a strong positive correlation between the expression of usp51,PD-L1 and ITGB1 was indicated in NSCLC patients with chemoresistance ***,the high expression of usp51,PD-L1 and ITGB1 are significantly correlated with a poor clinical *** conclusion,our data have demonstrated that the usp51/PD-L1/ITGB1 axis might play a key role in the malignant progression and therapeutic resistance in NSCLC,which can serve as a basis for the future development of therapeutic interventions in the treatment of advanced cancers.

关键词： NSCLC usp51 PD-L1 ITGB1 chemoresistance

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利用GEO数据集分析usp51在胃癌中的表达及临床意义

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现代肿瘤医学 2018年第20期26卷 3252-3256页

作者：臧丹曲秀娟王硕郭天舒杨子长徐璐李智刘云鹏中国医科大学附属第一医院肿瘤内科辽宁沈阳110001

目的:研究usp51在胃癌中的表达情况,探讨usp51表达与胃癌临床病理参数的相关性并预测usp51表达对胃癌预后评估的临床价值。方法:从人类肿瘤相关基因表达汇编(Gene Expression Omnibus,GEO)数据库下载胃癌样本数据集GSE62254的series mat... 详细信息

目的:研究usp51在胃癌中的表达情况,探讨usp51表达与胃癌临床病理参数的相关性并预测usp51表达对胃癌预后评估的临床价值。方法:从人类肿瘤相关基因表达汇编(Gene Expression Omnibus,GEO)数据库下载胃癌样本数据集GSE62254的series matrix数据,只保留临床资料和生存信息完整的患者病例,共收录胃癌患者295例。分析不同usp51表达与胃癌临床病理参数的相关性,以及对胃癌预后的影响。采用基因集富集分析方法分析和预测受usp51调控的相关基因。结果:usp51表达水平与胃癌患者年龄、T分期、p TNM分期及Lauren分型均有关(P均 0. 05)。随着usp51表达程度的增加,胃癌患者总生存时间(overall survival,OS)明显缩短(P usp51高表达富集了黏着斑通路、钙离子信号通路、细胞黏附分子和细胞外基质等相关的基因通路(P usp51高表达是一种预后不良因素,推测其可以作为判断胃癌患者预后的有效生物标志物以及治疗靶点。

关键词：胃癌人类肿瘤相关基因表达汇编 usp51 预后

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