Fibronectin stimulates human lung carcinoma cell growth by inducing cyclooxygenase-2 (cox-2) expression
Fibronectin stimulates human lung carcinoma cell growth by inducing cyclooxygenase-2 (cox-2) expression
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DOI：
10.1002/ijc.20281
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发表时间：
2004-09-01
影响因子：
6.4
通讯作者：
Roman, J
中科院分区：
文献类型：
--
作者：
Han, SW;Sidell, N;Roman, J
吸烟是肺癌发生的最重要的危险因素。与烟草相关的肺部疾病的共同特征之一是改变了肺结缔组织的含量和组成。特别是，烟草会导致纤连蛋白（FN）表达增加，纤连蛋白是一种与肺发育、损伤和修复以及肿瘤细胞侵袭有关的基质糖蛋白。我们推测肺中FN的过度沉积可能促进肺癌细胞增殖。与这一假设一致，我们发现 FN 在体外刺激人肺癌细胞增殖并减少细胞凋亡，这种作用是通过整合素 α5βI 介导的，并与环氧合酶-2 (COX-2) mRNA 和蛋白表达的上调以及前列腺素 E-2 (PGE(2)) 生物合成的增加有关。 FN 对 COX-2 的刺激作用被特异性 COX-2 抑制剂 NS-398 以及蛋白激酶 C (PKC)、Calphostin C 和细胞外信号调节激酶 (Erks)、PD98095 抑制剂阻断。电泳迁移率变动分析表明，FN 增加了环 AMP 反应元件结合蛋白 (CREB) 和 CCAAT/增强子结合蛋白 (C/EBP) 的核结合活性，这两种蛋白已知在 COX-2 启动子活性的调节中发挥重要作用。对人 COX-2 基因启动子的野生型和突变构建体进行的瞬时转染测定表明，当 CRE 或 NF-IL6 (C/EBP) 位点突变时，FN 的刺激作用被阻止。综上所述，结果表明 FN 通过诱导 COX-2 基因表达和 PGE2 生物合成来刺激人肺癌细胞增殖并减少细胞凋亡。 COX-2 基因启动子中 CRE 和 NF-IL6 (C/EBP) 位点的 PKC 和 Erk 激活以及 DNA-蛋白质相互作用似乎在此过程中发挥着关键作用。这项工作表明，由于基质糖蛋白纤连蛋白在肺中过度沉积而产生的特定基质结合βI整联蛋白（即α5βI）发出的信号可能会促进肺癌细胞的生长。 (C) 2004 Wiley-Liss, Inc.
Tobacco use is the most important risk factor for the development of lung carcinoma. One characteristic shared by tobacco-related lung diseases is altered lung connective tissue content and composition. In particular, tobacco results in increased expression of fibronectin (FN), a matrix glycoprotein implicated in lung development, injury and repair and in tumor cell invasion. We hypothesized that excessive deposition of FN in lung might promote lung carcinoma cell proliferation. Consistent with this hypothesis, we found that FN stimulated human lung carcinoma cell proliferation and diminished apoptosis in vitro, and that this effect was mediated through the integrin alpha5betaI and associated with upregulation of cyclooxygenase-2 (COX-2) mRNA and protein expression, and increased prostaglandin E-2 (PGE(2)) biosynthesis. The stimulatory effect of FN on COX-2 was blocked by the specific COX-2 inhibitor NS-398 and by inhibitors of protein kinase C (PKC), Calphostin C, and extracellular signal-regulated kinases (Erks), PD98095. Electrophoretic mobility shift assays revealed that FN increased the nuclear binding activity of cyclic AMP response element binding protein (CREB) and CCAAT/enhancer-binding protein (C/EBP), 2 proteins known to play important roles in the regulation of COX-2 promoter activity. Transient transfection assays with wildtype and mutated constructs of the human COX-2 gene promoter revealed that the stimulatory effect of FN was prevented when either the CRE or the NF-IL6 (C/EBP) sites were mutated. Taken together, the results indicate that FN stimulates human lung carcinoma cell proliferation and diminishes apoptosis by inducing COX-2 gene expression and PGE2 biosynthesis. Activation of PKC and Erk and DNA-protein interactions at CRE and NF-IL6 (C/EBP) sites in the COX-2 gene promoter appear to play key roles in this process. This work demonstrates that signaling through specific matrix-binding betaI integrins (i.e., alpha5betaI) resulting from exaggerated deposition in lung of the matrix glycoprotein fibronectin might promote lung carcinoma cell growth. (C) 2004 Wiley-Liss, Inc.