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Inflammatory response in the non-small cell lung tissue and its regulation for cancer treatment

非小细胞肺组织的炎症反应及其对癌症治疗的调节

基本信息

批准号：
15591479
负责人：
YOSHINO Ichiro
金额：
$ 2.05万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

项目摘要

Exp. 1:Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine derived from T cells and the pituitary gland. However, several types of solid cancers also secrete MIF, and this factor has been suggested to play an important role in carcinogenesis and the progression of malignancy. In this study, we quantified MIF mRNA expression of non-small cell lung cancer (NSCLC) tissues, and examined its relationship with clinicopathologic factors.Method: MIF mRNAs of both tumor and normal tissues were quantified by a real-time monitoring reverse transcription polymerase chain reaction in 59 patients with NSCLC. The relationship between the grade of MIF expression and clinicopathologic factors such as smoking history, cell type, stage, and prognosis was examined to investigate the clinical significance of intratumoral expression of MIF.Results: The mean copy number of MIF mRNA per 0.08 μg of total mRNA in tumor tissues was 144078.00, whereas that of normal lung tissue was 25438.46 … More (p< 0.0001). The amounts of MIF proteins revealed by a Western blot analysis were well correlated with those of the corresponding mRNAs. Male patients and heavy smokers showed significantly higher expression of MIF. And patients with squamous cell carcinomas showed a higher expression of MIF mRNA than other subjects. In squamous cell carcinoma patients, higher expression of MIF mRNA was significantly associated with unfavorable prognosis (p=0.0142).In a lung cancer cell line, PC9, tobacco smoke solution or benzo(a) pyrene induced MIF protein at a time-dependent manner.Conclusions : The general intratumoral expression and close relation to smoking suggested that MIF might contribute to tumorigenesis in the lung.Exp. 2From the results of the Exp. 1, it was suggested that cigarette smoke induced inflammatory cytokines such as MIF, and clinical survey of relationship between smoking status and postoperative prognosis in patients with non-small cell lung cancer.Methods: Lung adenocarcinoma cell lines (A549) were exposed to benzo(a)pyrene (B(a)P) for 24 weeks, and morphology, proliferative activity, and gene expression profiles were analyzed.Results: Although no apparent morphologic changes were observed, the B(A)P-exposed A549 exhibited enhanced proliferative activity in 1 % bovine serum medium, and dramatic changes in expression levels were observed in a large number of genes. Of them, epithelial-to-mesenchymal transition (EMT)-related genes such as migration stimulating factor, plasminogen activator-inhibitor, twist, transforming growth factor-beta, and basic fibroblast growth factor. Most enhanced expression levels remained 8 weeks after the retrieval of B(A)P in culture.Conclusions: B(a)P, which is one of the strongest carcinogens included in tobacco smoke, can induce EMT-related genes in lung cancer cells. This results indicate tobacco enhanced multiple factors including inflammatory cytokines (TGF-beta) and may drive malignant potential of lung cancer. Less

实验1：巨噬细胞迁移抑制因子（Macrophage migration inhibitory factor， MIF）是一种来源于T细胞和脑垂体的促炎细胞因子。然而，几种类型的实体癌也分泌MIF，并且该因子已被认为在癌变和恶性肿瘤进展中发挥重要作用。本研究通过定量分析非小细胞肺癌（NSCLC）组织中MIF mRNA的表达，并探讨其与临床病理因素的关系。方法：采用逆转录聚合酶链反应实时监测59例非小细胞肺癌患者肿瘤和正常组织的MIF mrna。观察MIF表达等级与吸烟史、细胞类型、分期、预后等临床病理因素的关系，探讨MIF在瘤内表达的临床意义。结果：肿瘤组织中MIF mRNA每0.08 μg拷贝数为144078.00，正常肺组织中MIF mRNA每0.08 μg拷贝数为25438.46…More （p< 0.0001）。Western blot分析显示MIF蛋白的数量与相应mrna的数量有很好的相关性。男性患者和重度吸烟者MIF表达明显增高。鳞状细胞癌患者的MIF mRNA表达高于其他受试者。在鳞状细胞癌患者中，MIF mRNA的高表达与不良预后显著相关（p=0.0142）。在肺癌细胞系中，PC9、烟草烟雾溶液或苯并(a)芘诱导MIF蛋白呈时间依赖性。结论：MIF在肿瘤内的普遍表达及其与吸烟的密切关系提示MIF可能参与肺部肿瘤的发生。2实验1的结果提示吸烟诱导炎性细胞因子如MIF，吸烟状况与非小细胞肺癌患者术后预后关系的临床调查。方法：将肺腺癌细胞（A549）暴露于苯并(a)芘（B(a)P）中24周，分析其形态、增殖活性和基因表达谱。结果：暴露于B(A) p的A549在1%牛血清培养基中增殖活性增强，大量基因表达水平发生显著变化，但未观察到明显的形态学变化。其中，上皮-间质转化（EMT）相关基因如迁移刺激因子、纤溶酶原激活因子-抑制剂、twist、转化生长因子- β、碱性成纤维细胞生长因子等。在培养中提取B(A)P后8周，大多数增强表达水平保持不变。结论：B(a)P是烟草烟雾中最强的致癌物之一，可诱导肺癌细胞中emt相关基因的表达。这些结果表明，烟草增加了包括炎症细胞因子（tgf - β）在内的多种因子，并可能驱动肺癌的恶性潜能。少