Tristetraprolin down-regulates interleukin-8 and vascular endothelial growth factor in malignant glioma cells

Malignant gliomas are highly aggressive tumors of the central nervous system that rely on production of growth factors for tumor progression. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and tumor necrosis factor-alpha, for example, are up-regulated in these tumors to promote angiogenesis and proliferation. RNA stability, mediated through adenine and uridine-rich elements (ARE) in the 3' untranslated region, is a critical control point for regulating these growth factors. RNA half-life is predominantly governed by a balance between stabilizing and destabilizing factors that bind to ARE. We have previously shown that the stabilizing factor HuR is overexpressed in malignant gliomas and linked to RNA stabilization of angiogenic growth factors. Here, we report that the destabilizing factor tristetraprolin (TTP) is also ubiquitously expressed in primary malignant glioma tissues and cell lines. In contrast to benign astrogliotic tissues, however, the protein was hyperphosphorylated, with evidence implicating the p38/mitogen-activated protein kinase (MAPK) pathway. Conditional overexpression of TTP as a transgene in malignant glioma cells led to RNA destabilization of IL-8 and VEGF and down-regulation of protein production. Analysis of in vivo RNA binding indicated a shift of mRNA toward ectopic TTP and away from endogenous HuR. This biochemical phenotype was associated with a decrease in cell proliferation, loss of cell viability, and apoptosis. We postulate that hyperphosphorylation of TTP via p38/MAPK promotes progression of malignant gliomas by negatively regulating its RNA destabilizing function.     

Paracrine interactions of vascular endothelial growth factor and platelet-derived growth factor in endothelial and lung cancer cells

While the effects of single growth factors on endothelial cells (ECs) have been extensively studied, the importance of induction of growth factors such as PDGF-BB (platelet derived growth factor) in ECs and its impact on tumor cell functions are only partly understood. Human umbilical vein endothelial cells (HUVECs) were cultured under serum-free conditions and stimulated by 20 ng/ml VEGF (vascular endothelial growth factor) or 20 ng/ml bFGF (basic fibroblastic growth factor). As determined by real-time PCR, both VEGF and bFGF induced a significant (up to 4-fold) increase in PDGF-B RNA expression which was time- and dose-dependent (p<0.05). Similarly, conditioned medium (CM) from lung cancer cells (A549) which is known to contain multiple growth factors including VEGF and bFGF also induced PDGF-B RNA expression. Using ELISA assays, VEGF and bFGF significantly increased PDGF-BB protein secretion in HUVECs (p<0.01). By addition of BIBF 1000, a novel inhibitor of the VEGF and bFGF receptor kinases, the effect of VEGF on PDGF-B RNA induction was significantly antagonized (p<0.01). Furthermore, we studied the biological significance of EC-derived PDGF-BB on lung cancer cells. Interestingly, HUVEC-derived CM significantly stimulated migration of A549 cells (p<0.001) with a trend to further increased migration with the use of VEGF-stimulated (PDGF-BB rich) CM (p=0.2). Collectively, endothelial and lung cancer cells seem to interact via various paracrine pathways, e.g. by the reciprocal induction of VEGF and PDGF-BB. Thus, targeting key molecules would result in expression alterations of multiple factors and alter the biological functions of both stromal and tumor cells.     

环氧合酶-2对胃癌血管内皮生长因子及血管形成的影响

 目的　探讨环氧合酶 2 (COX 2 )对胃癌血管内皮生长因子 (VEGF)的表达及血管生成的影响。方法　应用免疫组织化学技术检测胃癌组织中COX 2 ,VEGF表达和微血管密度 (MVD)。结果　COX 2在62 .2 %胃癌组织中表达增高 ,COX 2表达与VEGF表达显著相关 (γS=0 .5 85 ,P <0 .0 1 ) ,且COX 2和VEGF均阳性的胃癌组织MVD(64.0± 2 5 .4)亦明显高于两者均阴性者 (3 0 .7± 1 1 .5 ) (P <0 .0 1 )。结论　胃癌组织中存在COX 2的高表达 ,COX 2通过增加VEGF表达而促进肿瘤血管形成     

Serum vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) levels in small cell lung cancer

This study was conducted to determine the value of the angiogenic serum factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), in patients with small cell lung cancer (SCLC). These serum angiogenic factors were measured of 34 SCLC patients on the before and after chemotherapy in comparison with 20 healthy controls using ELISA method. Serum levels of VEGF and IL-8 were significantly increased in SCLC patients compared with healthy controls (p < 0.001). No statistically significant relationships was found between investigated elevated serum angiogenic parameters and various characteristics of patients and disease such as disease stage and tumor burden. Likewise, we also found no correlation between serum angiogenic factors. Cytotoxic therapy of patients was accompanied by unchanged serum levels of angiogenic factors. Contrary to serum IL-8, elevated serum levels of VEGF was determined as a prognostic factor for survival by univariate analysis (p = 0.05). Multivariate analysis revealed that independent prognostic factors of overall survival included only response to chemotherapy and weight loss (p < 0.001 for both). In conclusion, our data suggest that the angiogenic serum factors, VEGF and IL-8, are useful diagnostic factors, but not predictive and prognostic markers for overall survival in SCLC patients.     

反义寡核苷酸对 Lewis肺癌细胞合成VEGF的抑制作用

背景与目的 血管内皮生长因子(VEGF)是一种特异地作用于血管内皮细胞的生长因子,它能促进血管内皮细胞增殖及新生血管的生成.本研究的目的是探讨脂质体介导的VEGF反义硫代寡核苷酸(ASODN)对培养的Lewis肺癌细胞合成VEGF的影响.方法 将经脂质体包裹并经部分硫代修饰后的VEGF ASODN、正义寡核苷酸(SODN)加入培养的Lewis肺癌细胞中,采用RT-PCR技术和免疫组织化学SP法检测肺癌细胞中VEGF mRNA和VEGF蛋白表达,同时测定各上清液刺激下血管内皮细胞生长的受抑情况.结果 VEGF ASODN能明显抑制Lewis肺癌细胞VEGF mRNA和VEGF蛋白表达,而且可以显著抑制内皮细胞的生长.结论 VEGF ASODN能抑制肺癌细胞表达VEGF,可以成为肺癌基因治疗的一种新的途径.     

血管内皮生长因子与肺癌的关系

许多研究表明,新生毛细血管的形成对原发实体肿瘤细胞的增殖和生长是必不可少的,也是肿瘤侵袭转移的必须条件。同时,肿瘤的淋巴转移也是影响许多实体肿瘤发生、进展的一个重要因素。近年来的许多研究证实,血管内皮生长因子（vascular endothelial growth factor,VEGF）与肺癌新生血管和淋巴管的生长以及生物学行为密切相关。现就VEGF的结构功能特点与肺癌之间的关系分析报告如下。     

血管内皮生长因子对非小细胞肺癌术后生存率的影响

目的：研究血管内皮生长因子（ＶＥＧＦ）在非小细胞肺癌（ＮＳＣＬＣ）组织中的表达与预后。方法：用免疫组化技术测定１２７例ＮＳＣＬＣ的ＶＥＧＦ表达,并以Ｋａｐｌａｎ－Ｍｅｉｅｒ曲线描述生存率,Ｃｏｘ单、多因素分析ＶＥＧＦ表达与生存第的关系。结果：１２７例根治切除的非小细胞肺癌中,ＶＥＧＦ高表达者５２例,低表达者７５例,占４０．９％,经编译分析,ＶＥＧＦ表达与年龄、性别、病理类型、期别均无关;ＶＥＧＦ高     

The intratumoral expression of vascular endothelial growth factor and interleukin-8 associated with angiogenesis in nonsmall cell lung carcinoma patients.

BACKGROUND: Angiogenesis has important effects on tumor growth and metastasis. It is regulated by a variety of angiogenic and angiostatic factors. METHODS: To evaluate the effects of tumor cell-derived angiogenic factors, we performed an immunohistochemic study to evaluate the intratumoral expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in relation to intratumoral microvessel density (IMD) in tumors from 104 nonsmall cell lung carcinoma (NSCLC)patients. RESULTS: Fifty-four carcinomas were VEGF-positive, 47 carcinomas were IL-8-positive, and 53 carcinomas were hypervascular tumors. There was no significant correlation between the percentages of positive VEGF-staining and positive IL-8-staining in NSCLCs (rho = 0.174, P = 0.080). The IMD of VEGF-positive carcinomas was significantly greater than that of VEGF-negative carcinomas (P = 0.023). In addition, the IMD of IL-8-positive carcinomas was significantly greater than that of IL-8-negative carcinomas (P =0.013). The overall survival rate of patients with hypervascular tumors was significantly lower than that of patients with hypovascular tumors (41.0% versus 67.0%, P = 0.004). Cox proportional-hazards regression model also demonstrated that angiogenesis was one of the significant factors in predicting the survival of NSCLC patients (relative risk = 1.944, P = 0.041). CONCLUSIONS: Intratumoral expression of VEGF and IL-8 was associated with angiogenesis in NSCLCs. Tumor angiogenesis significantly affected the prognosis of NSCLC patients.     

非小细胞肺癌中血管内皮生长因子与树突细胞的关系

血管内皮生长因子(VEGF)是重要的肿瘤细胞生长因子之一,其可以抑制树突细胞(DC)的分化成熟,诱导成熟DC功能障碍,而DC亦可通过自分泌VEGF加重自身的功能障碍,从而介导肿瘤细胞逃逸免疫监视.因此VEGF和DC的相互关系与非小细胞肺癌(NSCLC)的分化程度、淋巴结转移、临床分期密切相关.二者关系可为临床NSCLC的治疗提供相应理论依据.     

Melatonin inhibits the expression of vascular endothelial growth factor in pancreatic cancer cells

Objective:To investigate the effects of melatonin on cellular proliferation and endogenous vascular endothelial growth factor(VEGF) expression in pancreatic carcinoma cells(PANC-1).Methods:PANC-1 cells were cultured for this study.The secreted VEGF concentration in the culture medium was determined using ELISA method,VEGF production in the tumor cells was detected by immunocytochemistry,and VEGF mRNA expression was determined by RT-PCR.Results:Higher melatonin concentrations significantly inhibited cellular proliferation,with 1 mmol/L concentration exhibiting the highest inhibitory effect(P<0.01).VEGF concentrations in the cell culture supernatants and intra-cellules were all significantly reduced after melatonin(1 mmol/L) incubation(P<0.05).VEGF mRNA expression decreased markedly in a time-dependent manner during the observation period(P<0.05).Conclusions:High melatonin concentrations markedly inhibited the proliferation of pancreatic carcinoma cells.The endogenous VEGF expression was also suppressed by melatonin incubation.     

nm23和血管内皮生长因子表达在非小细胞肺癌中的意义

目的 研究非小细胞肺癌(NSCLC)的预后与nm23及血管内皮生长因子(VEGF)表达间的关系。方法 对81例行手术治疗的NSCLV患者运用免疫组织化学的方法检测nm23和VEGF的表达。检测nm23、VEGF使用抗-nm23及抗-VEGF单克隆抗体。结果 在术后半年出现转移的32例NSCLC中,nm23阳性率为43％(14/32),较术后未出现转移者(71％,35/49)明显减低(P=0.004)。在32例术后半年出现转移组中,VEGF表达阳性率为75％(24/32),在49例术后未出现转移组中,VEGF表达阳性率51％(25/49)。经统计学处理,差异有显著性(P=0.031)。结论 NSCLC术后转移组nm23低表达,VEGF高表达。两指标联合应用可作为预测NSCLC预后的比较客观的指标。     

COX-2与VEGF在人肺癌组织中的表达

背景与目的　已有研究发现环氧化酶2(COX 2)和血管内皮生长因子(VEGF)在肿瘤组织中有高表达且对患者的预后有重要影响。本研究拟探讨肺癌组织中COX 2及VEGF的表达及作用。方法　应用组织芯片技术制成126例肺癌组织芯片,采用免疫组化方法对标本中COX 2及VEGF的表达进行检测,并对COX 2的表达情况与疾病生物学特点、患者生存时间等关系进行了回顾性队列研究。结果　COX 2 阳性表达86例(68.25%)。COX 2在肿瘤中的表达与肿瘤T分期、N分期及疾病临床分期等具有密切关系(P<0.05)。VEGF同样在肺癌组织中有高表达(98/126,77.78%),且与COX 2的表达在统计学上具有显著正相关(χ2=6.72,P<0.05)。COX 2和VEGF表达水平与患者生存时间有密切关系(P<0.05)。结论　COX 2与VEGF在人肺癌组织中均有高表达,两者能分别作为患者生存时间预测的单因素影响因子,且同是外科手术切除后的肺癌病例预后较差的标志。     

VIP增强VEGF mRNA在非小细胞肺癌细胞中的表达

背景与目的研究发现血管内皮生长因子(VEGF)和血管活性肠肽(VIP)均对肿瘤的生长具有促进作用,但VIP通过何种方式来促进肿瘤的生长还不清楚。本研究的目的是观察VIP对非小细胞肺癌(NSCLC)细胞中VEGFmRNA表达的影响。方法应用反转录聚合酶链式反应(RTPCR)技术检测VEGFmRNA在NSCLC细胞系和小细胞肺癌(SCLC)细胞系中的表达及VIP对其表达的影响。结果在NSCLC细胞系A549、GLC82、H157、H460和SCLC细胞系H446中检测到了VEGFmRNA的表达。VIP能促进VEGFmRNA在A549和H157细胞中的表达,在VIP作用8h和16h时,VEGFmRNA的表达水平达到最高,显著高于VIP作用0h时(P<0.01)。结论VIP可能通过增强VEGFmRNA在肺癌细胞中的表达和分泌,促进肺癌新生血管的生成,参与肿瘤的生长。