星形胶质细胞瘤分泌一氧化氮促进炎性水肿带相关肿瘤微环境的研究  

Nitric Oxide Secreted From Astrocytoma Promotes Inflammatory Edema Zone of Tumor Microenvironment

作　　者：李春涛[1,4] 张其健 张李洋[1,4] 付思祺 曾瑜[1,4] LI Chun-Tao;ZHANG Qi-Jian;ZHANG Li-Yang;FU Si-Qi;ZENG Yu(Department of Neurosurgery,Xiangya Hospital,Central South University,Changsha 410008,China;Wound Center,Xiangya Hospital,Central South University,Changsha 410008,China;Department of Dermatology,Hunan Key Laboratory of Medical Epigenomics,The Second Xiangya Hospital,Central South University,Changsha 410011,China;National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha 410008,China)

机构地区：[1]中南大学湘雅医院神经外科,长沙410008 [2]中南大学湘雅医院伤口中心,长沙410008 [3]中南大学湘雅二医院皮肤科,表观遗传湖南省重点实验室,长沙410011 [4]国家老年病学临床医学研究中心,长沙410008

出　　处：《生物化学与生物物理进展》2022年第11期2181-2191,共11页Progress In Biochemistry and Biophysics

基　　金：湖南省自然科学基金(2021JJ70150,2022JJ70155,2018JJ6063);长沙市自然科学基金(kq2202376)。

摘　　要：目的检测在星形胶质细胞瘤中一氧化氮(nitric oxide,NO)的表达及促进炎性水肿带相关肿瘤微环境的作用。方法收集27例星形胶质细胞瘤患者的临床资料和肿瘤标本(WHO Ⅱ级10例、Ⅱ-Ⅲ级7例、Ⅳ级10例),磁共振成像确认水肿带及手术取材部位;格里斯试剂比色法检测亚硝酸盐含量;质谱分析不同级别星形胶质细胞瘤(不同级别各5例)水肿带炎性分子含量;通过ClusterProfiler包以及Proteomaps和Metascape网页工具进行富集分析预测肿瘤分泌的NO与微环境中互作的蛋白质。结果星形胶质细胞瘤组织及水肿带中存在NO,胶质瘤组织中的NO高于水肿带中的NO。在WHO Ⅱ-Ⅲ级和WHO Ⅳ级胶质瘤的水肿带中,有大量超氧化物歧化酶、细胞色素C氧化酶、热休克蛋白、CD44抗原,白介素-8、白介素-24、凝溶胶蛋白、应激诱导磷酸蛋白1、丝裂原活化蛋白激酶、硫氧还蛋白过氧化物酶、S100蛋白等炎症相关蛋白质的表达。信号通路分析提示,与Ⅱ-Ⅲ级别星形胶质细胞瘤相比,Ⅳ级胶质母细胞瘤水肿带中的基因更多地参与无氧代谢,如糖酵解。更重要的是,这些目标基因显著参与多种氧化还原反应,如氧化还原酶活性和过氧化物酶活性。其中,诱导性一氧化氮合酶(inducible NOS,iNOS)、NO、过氧亚硝酸阴离子(ONOO^(-))、铜/锌超氧化物歧化酶(Cu/Zn superoxide dismutase,SOD-1)在氧化还原反应中发挥重要作用。结论星形胶质细胞瘤周围水肿带的形成是炎症反应的结果,胶质瘤细胞通过分泌NO调控SOD-1等炎性分子促进侵袭性炎性肿瘤微环境的形成。Objective This study aimed to investigate the expression and proinflammation effect of nitric oxide in the edema of astrocytoma.Methods WHO Ⅱ(10 cases),Ⅱ-Ⅲ(7 cases),and Ⅳ(10 cases)grade astrocytoma peritumor edema tissues were identified by magnetic resonance imaging(MRI)and collected after surgery.The content of nitrite was detected by Grice reagent;HPLC-MS/MS was applied to identify inflammatory molecules in edema zone(5 cases of each grade);ClusterProfiler,Proteomaps and Metascapedatasets were used to investigate the potential protein network between NO and microenvironment.Results There was NO in astrocytoma and edema zone,and NO in glioma was higher than that in edema zone,which had cytochrome coxidase(COX),heat shock protein(HSP),CD44 antigen(CD44),interleukin-8(IL-8),interleukin-24(IL-24),gelsolin(GSN),stress-induced-phosphoprotein 1(STIP1),mitogen-activated protein kinase 1(MAPK1),peroxiredoxin(PRDX),protein S100,and superoxide dismutase(SOD).Enrichment analysis demonstrated that proteins in glioblastoma were more involved in anaerobic metabolism than grade Ⅱ-Ⅲ astrocytoma,such as glycolysis.More importantly,these proteins were significantly involved in various redox reactions,such as oxidoreductase activity and peroxidase activity among which iNOS,NO,ONOO-and SOD-1 played a vital role in redox reactions.Conclusion The formation of edema zone around astrocytoma was formed by inflammatory reaction.Astrocytoma cells regulated SOD-1 and other inflammatory molecules by secreting NO to promote the formation of invasive inflammatory tumor microenvironment.

关 键 词：胶质瘤 一氧化氮 水肿带 炎性微环境 

分 类 号：R739.41[医药卫生—肿瘤]