信号转导及转录激活子1和3在高迁移率族蛋白1诱导的大鼠纤维母细胞样滑膜细胞增殖中的作用

目的探讨高迁移率族蛋白（high mobility group box,HMGB）1对大鼠滑膜细胞STAT信号通路的调控作用。方法将常规培养大鼠滑膜细胞株RSC-364细胞随机分为正常对照组和10μg／LHMGBI刺激组,分别培养6h、12h和24h,RT—PCR检测STAT1／3mRNA的表达,Western印迹法和流式细胞术（flow cytometric analysis,FCM）检测STAT1、STAT3、磷酸化STAT1（phospho—STAT1,p—STAT1）和磷酸化3（phospho—STAT3,p—STAT3）蛋白的表达,免疫细胞化学（ICC）检测PCNA蛋白的表达。结果HMGB1刺激6h～24h组STAT1 mRNA和p-STAT1蛋白的相对表达量呈时间依赖性上调,24h表达最高,与正常对照组相比差异均具有显著统计学意义（P〈0．05,P〈0．01）。PCNA蛋白阳性信号表达于细胞核内,呈棕黄色颗粒,且随着刺激时间延长阳性信号逐渐增强。RT—PCR、ICC染色和FCM均显示STAT3mR—NA和p-STAT3蛋白的相对表达量各组间相比差异均无统计学意义。结论HMGB1可能通过激活STAT1信号转导通路促进滑膜细胞的增殖和分化。     

信号转导与转录活化蛋白STAT3在肿瘤发生中的作用

STAT3是信号转导与转录活化蛋白（STAT）家族的一个重要成员,也是一个可以被多种调控细胞增殖、分化、发育、存活和炎症的细胞因子、生长因子及肿瘤蛋白所激活的关键信号转导蛋白。在多种肿瘤细胞、细胞性状转化过程和肿瘤形成过程中可以检测到组成性激活的STAT3。我们从STAT3在肿瘤细胞中组成性激活的机制、STAT3作为转录因子对肿瘤细胞调控的机制等方面对STAT3在肿瘤发生中的作用进行简要综述。     

Genetic regulation of MUC1 expression by Helicobacter pylori in gastric cancer cells

Helicobacter pylori infection of the stomach is associated with the development of gastritis, peptic ulcers, and gastric adenocarcinomas, but the mechanisms are unknown. MUC1 is aberrantly overexpressed by more than 50% of stomach cancers, but its role in carcinogenesis remains to be defined. The current studies were undertaken to identify the genetic mechanisms regulating H. pylori-dependent MUC1 expression by gastric epithelial cells. Treatment of AGS cells with H. pylori increased MUC1 mRNA and protein levels, and augmented MUC1 gene promoter activity, compared with untreated cells. H. pylori increased binding of STAT3 and MUC1 itself to the MUC1 gene promoter within a region containing a STAT3 binding site, and decreased CpG methylation of the MUC1 promoter proximal to the STAT3 binding site, compared with untreated cells. These results suggest that H. pylori upregulates MUC1 expression in gastric cancer cells through STAT3 and CpG hypomethylation.     

NADPH-oxidase-dependent reactive oxygen species mediate EGFR transactivation by FPRL1 in WKYMVm-stimulated human lung cancer cells

Cross talk between unrelated cell surface receptors, such as G-protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTK), is a crucial signaling mechanism to expand the cellular communication network. We investigated the ability of the GPCR formyl peptide receptor-like 1 (FPRL1) to transactivate the RTK epidermal growth factor receptor (EGFR) in CaLu-6 cells. We observed that stimulation with WKYMVm, an FPRL1 agonist isolated by screening synthetic peptide libraries, induces EGFR tyrosine phosphorylation, p47^phox phosphorylation, NADPH-oxidase-dependent superoxide generation, and c-Src kinase activity. As a result of EGFR transactivation, phosphotyrosine residues provide docking sites for recruitment and triggering of the STAT3 pathway. WKYMVm-induced EGFR transactivation is prevented by the FPRL1-selective antagonist WRWWWW, by pertussis toxin (PTX), and by the c-Src inhibitor PP2. The critical role of NADPH-oxidase-dependent superoxide generation in this cross-talk mechanism is corroborated by the finding that apocynin or a siRNA against p22^phox prevents EGFR transactivation and c-Src kinase activity. In addition, WKYMVm promotes CaLu-6 cell growth, which is prevented by PTX and by WRWWWW. These results highlight the role of FPRL1 as a potential target of new drugs and suggest that targeting both FPRL1 and EGFR may yield superior therapeutic effects compared with targeting either receptor separately.