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

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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