Studies on the expression of endothelin, its receptor subtypes, and converting enzymes in lung cancer and in human bronchial epithelium
Studies on the expression of endothelin, its receptor subtypes, and converting enzymes in lung cancer and in human bronchial epithelium
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DOI：
10.1165/ajrcmb.22.4.3795
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发表时间：
2000-04-01
影响因子：
6.4
通讯作者：
Woll, PJ
中科院分区：
文献类型：
--
作者：
Ahmed, SI;Thompson, J;Woll, PJ
肺癌，特别是小细胞肺癌（SCLC）的特征在于产生许多肽及其导致的临床综合征。这些肽可以作为这些肿瘤的自分泌生长因子。在这项研究中，我们研究了内皮素（ET）-1在肺癌中的作用。使用逆转录/聚合酶链反应（RT-PCR），酶联免疫吸附试验和免疫细胞化学，我们筛选了一组肺癌细胞系的ET-1，其受体和内皮素转换酶-1（ECE-1），它产生的ET-1的活性形式。ET-1信使RNA在7例SCLC中的5例，4例非小细胞肺癌（NSCLC）和人支气管上皮（HBE）细胞中表达。如果自分泌生长环发挥作用，ECE-1的细胞内同种型在处理ET-1中很重要，与细胞外同种型的表达相比，ECE-1在肺癌细胞系中下调。内皮素A受体（ETAR），它介导的ET-1在前列腺癌和卵巢癌中的促有丝分裂作用，在HBE细胞中的表达上调相比，在三个7 SCLC和两个4 NSCLC细胞系。内皮素B受体（ETBR）更广泛，在7/7例SCLC、4/4例NSCLC和HBE细胞中表达。我们使用流式细胞术测量细胞内钙的动员作为ETAR的功能测定。这些结果与RT-PCR结果一致，表明ETAR在肺癌中表达下调或参与了另一条信号转导途径，未发现功能性受体介导自分泌生长环的证据，因此我们的研究结果不支持ET-1在肺癌中的功能性自分泌生长作用。相反，我们建议，ET-1可能作为一个旁分泌的生长因子，周围的上皮细胞和内皮细胞通过替代途径，促进血管生成和基质生长。
Lung cancer, particularly small cell lung cancer (SCLC), is characterized by production of numerous peptides and their resulting clinical syndromes. Such peptides can act as autocrine growth factors for these tumors. In this study, we investigated the role of endothelin (ET)-1 in lung cancer. Using reverse transcription/polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay, and immunocytochemistry, we screened a panel of lung cancer cell lines for ET-1, its receptors, and endothelin converting enzyme-1 (ECE-1), which generates the active form of ET-1. ET-1 messenger RNA was expressed in five of seven SCLC, four of four non-small cell lung cancer (NSCLC), and human bronchial epithelial (HBE) cells. The intracellular isoform of ECE-1, important in processing ET-1 if an autocrine growth loop is to function, was downregulated in the lung cancer cell lines as compared with expression of the extracellular isoform. Endothelin A receptor (ETAR), which mediates the mitogenic effects of ET-1 in prostate and ovarian cancer, was upregulated in HBE cells compared with expression in three of seven SCLC and two of four NSCLC cell lines. Endothelin B receptor (ETBR) was more widespread, being expressed in seven of seven SCLC, four of four NSCLC, and the HBE cells. We used flow cytometry to measure mobilization of intracellular calcium as a functional assay for the ETAR. These data concurred with the RT-PCR results, indicating that the ETAR was downregulated or was involved in an alternative signal transduction pathway in lung cancer, and no evidence of functional receptor mediating an autocrine growth loop was found. From our study, the data do not support the putative functional autocrine growth role of ET-1 in lung cancer. We propose instead that ET-1 may act as a paracrine growth factor for surrounding epithelial and endothelial cells via alternative pathways, promoting angiogenesis and stromal growth.