Jakowlew S B, Mariano J M, You L, Mathias A
National Cancer Institute, Medicine Branch, Rockville, MD 20850, USA.
Biochim Biophys Acta. 1997 Aug 7;1353(2):157-70. doi: 10.1016/s0167-4781(97)00068-7.
In addition to autoregulating its own expression, transforming growth factor-beta 1 (TGF-beta1) also regulates the production of proteases, protease inhibitors and extracellular matrix proteins. To investigate the relationship between plasminogen activator (PA), plasminogen activator inhibitor-1 (PAI-1) and the extracellular matrix in malignant and normal lung epithelial cells and to determine whether malignant lung epithelial cells may be more invasive than normal lung epithelial cells because of differences in expression of these proteins in response to TGF-beta, the regulation of PA, PAI-1, fibronectin, laminin and thrombospondin by TGF-beta1 in human non-small cell lung cancer (NSCLC) cells was examined and compared with normal human bronchial epithelial (NHBE) cells. TGF-beta1 caused a persistent increase in expression of the mRNAs for both PA and PAI-1 in NSCLC cells, with the increase in PAI-1 mRNA beginning several hours before that of PA mRNA. By immunoprecipitation analysis, it was shown that TGF-beta1 also induced a corresponding increase in the amount of PAI-1 protein in these NSCLC cells as well. In contrast, while TGF-beta1 also increased expression of PAI-1 mRNA in NHBE cells, expression of PA mRNA decreased simultaneously. Treatment of NSCLC cells with TGF-beta1 resulted in a persistent increase in expression of the mRNAs for fibronectin, laminin and thrombospondin; expression of fibronectin protein also increased after treatment with TGF-beta1 in these cells. When NHBE cells were similarly cultured in the presence of TGF-beta1, expression of fibronectin mRNA also increased in a persistent manner; however, only an early transient increase in the level of the mRNAs for laminin and thrombospondin was detected in these cells. These data show that there is differential regulation of the genes for PA and PAI-1 and the extracellular matrix protein fibronectin in response to TGF-beta1 not only when NSCLC and NHBE cells are compared, but also when different NSCLC cells are compared with each other.
除了自身调节其表达外，转化生长因子-β1（TGF-β1）还调节蛋白酶、蛋白酶抑制剂和细胞外基质蛋白的产生。为了研究恶性和正常肺上皮细胞中纤溶酶原激活物（PA）、纤溶酶原激活物抑制剂-1（PAI-1）与细胞外基质之间的关系，并确定恶性肺上皮细胞是否由于这些蛋白在对TGF-β反应中的表达差异而比正常肺上皮细胞更具侵袭性，研究了TGF-β1对人非小细胞肺癌（NSCLC）细胞中PA、PAI-1、纤连蛋白、层粘连蛋白和血小板反应蛋白的调节作用，并与正常人支气管上皮（NHBE）细胞进行了比较。TGF-β1导致NSCLC细胞中PA和PAI-1的mRNA表达持续增加，PAI-1 mRNA的增加比PA mRNA早数小时开始。通过免疫沉淀分析表明，TGF-β1也诱导这些NSCLC细胞中PAI-1蛋白量相应增加。相比之下，虽然TGF-β1也增加了NHBE细胞中PAI-1 mRNA的表达，但PA mRNA的表达同时下降。用TGF-β1处理NSCLC细胞导致纤连蛋白、层粘连蛋白和血小板反应蛋白的mRNA表达持续增加；这些细胞在用TGF-β1处理后纤连蛋白蛋白的表达也增加。当NHBE细胞在TGF-β1存在下进行类似培养时，纤连蛋白mRNA的表达也持续增加；然而，在这些细胞中仅检测到层粘连蛋白和血小板反应蛋白的mRNA水平早期短暂增加。这些数据表明，不仅在比较NSCLC和NHBE细胞时，而且在相互比较不同的NSCLC细胞时，PA和PAI-1以及细胞外基质蛋白纤连蛋白的基因对TGF-β1的反应存在差异调节。
