目的研究气体皮膜蛋白B(Gasdermin B,GSDMB)在卵巢癌中的临床价值及其与免疫浸润关系,探索卵巢癌新的免疫治疗标志物。方法使用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库中基因表达矩阵、体细胞突变、体细胞拷贝数变异(somat...目的研究气体皮膜蛋白B(Gasdermin B,GSDMB)在卵巢癌中的临床价值及其与免疫浸润关系,探索卵巢癌新的免疫治疗标志物。方法使用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库中基因表达矩阵、体细胞突变、体细胞拷贝数变异(somatic copy number alteration,SCNA)和临床信息数据,GISTIC(Genomic Identification of Significant Targets in Cancer)算法进行拷贝数分析,使用CIBERSORT(Cell-type Identification by Estimating Relative Subsets of RNA Transcripts)算法量化肿瘤微环境(tumor microenvironment,TME)中22种免疫细胞的相对丰度,通过蛋白质互作(protein-protein interaction,PPI)分析探寻GSDMB相关互作蛋白,通过多色免疫荧光技术验证GSDMB蛋白在不同免疫类型卵巢癌临床样本中的空间分布差异及与免疫细胞的作用关系。结果在卵巢癌患者中,GSDMB基因在癌旁组织的表达水平显著高于癌组织(P<0.001)。高表达GSDMB的患者表现出更高水平的免疫趋化因子(如CXCL9、CXCL10,P<0.01)和肿瘤杀伤性淋巴细胞(CD8+T细胞占比高于低表达组,P<0.001)。GSDMB基因拷贝数变异显著影响免疫细胞浸润水平,其中GSDMB拷贝数扩增的患者CD4+T细胞和树突状细胞的浸润水平降低(P<0.05),而GSDMB深度缺失组CD8+T细胞和中性粒细胞浸润程度显著减少(P<0.01)。PPI网络分析发现,GSDMB可能与多个重要的免疫分子如IL-37、IL-18BP、IL-33和IL-2发生蛋白互作(Pearson相关性r>0.6,P<0.001)。多色免疫荧光分析显示,GSDMB高表达的肿瘤更倾向于免疫炎症型(52.6%),而低表达组中免疫沙漠型占比更高(47.3%)。免疫治疗队列分析表明,GSDMB可作为免疫治疗响应性的潜在预测因子,其在多个免疫检查点抑制剂(PD-1/PD-L1/CTLA4)治疗队列中的预测效能较高(AUC>0.8)。结论GSDMB对卵巢癌TME重塑具有重要作用,可能是免疫治疗增敏新靶标。展开更多
细胞焦亡是一种炎症性程序性死亡方式,是一种有别于传统的坏死、凋亡等的新型细胞死亡方式,主要由成孔蛋白Gasdermin (GSDM)家族介导。活化的半胱氨酸天冬氨酸特异性蛋白酶(caspase)切割Gasdermin家族成员释放N端结构域在胞膜上打孔,从...细胞焦亡是一种炎症性程序性死亡方式,是一种有别于传统的坏死、凋亡等的新型细胞死亡方式,主要由成孔蛋白Gasdermin (GSDM)家族介导。活化的半胱氨酸天冬氨酸特异性蛋白酶(caspase)切割Gasdermin家族成员释放N端结构域在胞膜上打孔,从而导致细胞肿胀破裂死亡。Gasdermin B (GSDMB)属于Gasdermin (GSDM)家族,具有促肿瘤或抗肿瘤作用。在肿瘤细胞的相关研究中发现,GSDMB在乳腺癌、胃癌、肝癌、宫颈癌和结肠癌等癌细胞中高表达。因此,学者们认为GSDMB可能作为癌基因参与了癌症的进展和转移。本文综述了GSDMB在各种恶性肿瘤中的作用,以期为肿瘤的临床诊断、治疗及预后提供新的思路。Pyroptosis is an inflammatory programmed cell death, which is different from traditional necrosis and apoptosis. It is mainly mediated by the poreforming protein Gasdermin (GSDM) family. Activated caspases cleave Gasdermin family members to release N-terminal domains that punch holes in the cell membrane, leading to cell swelling, rupture and death. Gasdermin B (GSDMB) belongs to the Gasdermin (GSDM) family and has pro-or anti-tumor effects. Studies on tumor cells have found that GSDMB is highly expressed in breast cancer, gastric cancer, liver cancer, cervical cancer and colon cancer cells. Therefore, scholars believe that GSDMB may be involved in cancer progression and metastasis as an oncogene. This article reviews the role of GSDMB in various malignant tumors, in order to provide new ideas for the clinical diagnosis, treatment and prognosis of tumors.展开更多
Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, ...Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, does not induce cell death. Here, we show that GSDMB is highly expressed in the leukocytes of septic shock patients, which is associated with increased release of the gasdermin D (GSDMD) N-terminus. GSDMB expression and the accumulation of the N-terminal fragment of GSDMD are induced by the activation of the non-canonical pyroptosis pathway in a human monocyte cell line. The downregulation of GSDMB alleviates the cleavage of GSDMD and cell death. Consistently, the overexpression of GSDMB promotes GSDMD cleavage, accompanied by increased LDH release. We further found that GSDMB promotes caspase-4 activity, which is required for the cleavage of GSDMD in non-canonical pyroptosis, by directly binding to the CARD domain of caspase-4. Our study reveals a GSDMB-mediated novel regulatory mechanism for non-canonical pyroptosis and suggests a potential new strategy for the treatment of inflammatory diseases.展开更多
Asthma is a chronic respiratory disease,and clinically,asthma exacerbations remain difficult to treat.The disease is caused by combinations of and interactions between genetic and environmental factors.Genomic and gen...Asthma is a chronic respiratory disease,and clinically,asthma exacerbations remain difficult to treat.The disease is caused by combinations of and interactions between genetic and environmental factors.Genomic and genetic approaches identified many novel genes to treat asthma and brought new insights into the disease.The products of the genes have functional roles in regulating physiological or pathophysiological processes in airway structural cells and immune system cells.Genetic factors also interact with environmental factors such as air pollutants,and bacterial and viral infections to trigger the disease.Thymic stromal lymphopoietin(TSLP),orosomucoid-like 3(ORMDL3),and gasdermin B(GSDMB)are three genes identified by genetic studies to have a great potential as therapeutic targets of asthma.TSLP is an important driver of type 2 inflammation.ORMDL3 mediates cell stress,sphingolipid synthesis,and viral and bacterial infections.GSDMB regulates cell pyroptosis through its N and C terminals and can bind sulfatides to influence inflammatory response.Investigating inhibitors or modulators for these pathways would bring a new landscape for therapeutics of asthma in future.展开更多
文摘目的研究气体皮膜蛋白B(Gasdermin B,GSDMB)在卵巢癌中的临床价值及其与免疫浸润关系,探索卵巢癌新的免疫治疗标志物。方法使用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库中基因表达矩阵、体细胞突变、体细胞拷贝数变异(somatic copy number alteration,SCNA)和临床信息数据,GISTIC(Genomic Identification of Significant Targets in Cancer)算法进行拷贝数分析,使用CIBERSORT(Cell-type Identification by Estimating Relative Subsets of RNA Transcripts)算法量化肿瘤微环境(tumor microenvironment,TME)中22种免疫细胞的相对丰度,通过蛋白质互作(protein-protein interaction,PPI)分析探寻GSDMB相关互作蛋白,通过多色免疫荧光技术验证GSDMB蛋白在不同免疫类型卵巢癌临床样本中的空间分布差异及与免疫细胞的作用关系。结果在卵巢癌患者中,GSDMB基因在癌旁组织的表达水平显著高于癌组织(P<0.001)。高表达GSDMB的患者表现出更高水平的免疫趋化因子(如CXCL9、CXCL10,P<0.01)和肿瘤杀伤性淋巴细胞(CD8+T细胞占比高于低表达组,P<0.001)。GSDMB基因拷贝数变异显著影响免疫细胞浸润水平,其中GSDMB拷贝数扩增的患者CD4+T细胞和树突状细胞的浸润水平降低(P<0.05),而GSDMB深度缺失组CD8+T细胞和中性粒细胞浸润程度显著减少(P<0.01)。PPI网络分析发现,GSDMB可能与多个重要的免疫分子如IL-37、IL-18BP、IL-33和IL-2发生蛋白互作(Pearson相关性r>0.6,P<0.001)。多色免疫荧光分析显示,GSDMB高表达的肿瘤更倾向于免疫炎症型(52.6%),而低表达组中免疫沙漠型占比更高(47.3%)。免疫治疗队列分析表明,GSDMB可作为免疫治疗响应性的潜在预测因子,其在多个免疫检查点抑制剂(PD-1/PD-L1/CTLA4)治疗队列中的预测效能较高(AUC>0.8)。结论GSDMB对卵巢癌TME重塑具有重要作用,可能是免疫治疗增敏新靶标。
文摘细胞焦亡是一种炎症性程序性死亡方式,是一种有别于传统的坏死、凋亡等的新型细胞死亡方式,主要由成孔蛋白Gasdermin (GSDM)家族介导。活化的半胱氨酸天冬氨酸特异性蛋白酶(caspase)切割Gasdermin家族成员释放N端结构域在胞膜上打孔,从而导致细胞肿胀破裂死亡。Gasdermin B (GSDMB)属于Gasdermin (GSDM)家族,具有促肿瘤或抗肿瘤作用。在肿瘤细胞的相关研究中发现,GSDMB在乳腺癌、胃癌、肝癌、宫颈癌和结肠癌等癌细胞中高表达。因此,学者们认为GSDMB可能作为癌基因参与了癌症的进展和转移。本文综述了GSDMB在各种恶性肿瘤中的作用,以期为肿瘤的临床诊断、治疗及预后提供新的思路。Pyroptosis is an inflammatory programmed cell death, which is different from traditional necrosis and apoptosis. It is mainly mediated by the poreforming protein Gasdermin (GSDM) family. Activated caspases cleave Gasdermin family members to release N-terminal domains that punch holes in the cell membrane, leading to cell swelling, rupture and death. Gasdermin B (GSDMB) belongs to the Gasdermin (GSDM) family and has pro-or anti-tumor effects. Studies on tumor cells have found that GSDMB is highly expressed in breast cancer, gastric cancer, liver cancer, cervical cancer and colon cancer cells. Therefore, scholars believe that GSDMB may be involved in cancer progression and metastasis as an oncogene. This article reviews the role of GSDMB in various malignant tumors, in order to provide new ideas for the clinical diagnosis, treatment and prognosis of tumors.
基金the Ministry of Science and Technology of China (2015BAI08B02 and 2014BAI02B01)the National Natural Science Foundation of China (31772550, 31301217,81772052, and 31500944)the Natural Science Foundation of Jiangsu Province (BK20181260).
文摘Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, does not induce cell death. Here, we show that GSDMB is highly expressed in the leukocytes of septic shock patients, which is associated with increased release of the gasdermin D (GSDMD) N-terminus. GSDMB expression and the accumulation of the N-terminal fragment of GSDMD are induced by the activation of the non-canonical pyroptosis pathway in a human monocyte cell line. The downregulation of GSDMB alleviates the cleavage of GSDMD and cell death. Consistently, the overexpression of GSDMB promotes GSDMD cleavage, accompanied by increased LDH release. We further found that GSDMB promotes caspase-4 activity, which is required for the cleavage of GSDMD in non-canonical pyroptosis, by directly binding to the CARD domain of caspase-4. Our study reveals a GSDMB-mediated novel regulatory mechanism for non-canonical pyroptosis and suggests a potential new strategy for the treatment of inflammatory diseases.
文摘Asthma is a chronic respiratory disease,and clinically,asthma exacerbations remain difficult to treat.The disease is caused by combinations of and interactions between genetic and environmental factors.Genomic and genetic approaches identified many novel genes to treat asthma and brought new insights into the disease.The products of the genes have functional roles in regulating physiological or pathophysiological processes in airway structural cells and immune system cells.Genetic factors also interact with environmental factors such as air pollutants,and bacterial and viral infections to trigger the disease.Thymic stromal lymphopoietin(TSLP),orosomucoid-like 3(ORMDL3),and gasdermin B(GSDMB)are three genes identified by genetic studies to have a great potential as therapeutic targets of asthma.TSLP is an important driver of type 2 inflammation.ORMDL3 mediates cell stress,sphingolipid synthesis,and viral and bacterial infections.GSDMB regulates cell pyroptosis through its N and C terminals and can bind sulfatides to influence inflammatory response.Investigating inhibitors or modulators for these pathways would bring a new landscape for therapeutics of asthma in future.
