Differential regulation of nonsteroidal anti-inflammatory drug-activated gene in normal human tracheobronchial epithelial and lung carcinoma cells by retinoids
Differential regulation of nonsteroidal anti-inflammatory drug-activated gene in normal human tracheobronchial epithelial and lung carcinoma cells by retinoids
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DOI：
10.1124/mol.63.3.557
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发表时间：
2003-03-01
影响因子：
3.6
通讯作者：
Jetten, AM
中科院分区：
文献类型：
--
作者：
Newman, D;Sakaue, M;Jetten, AM
在这项研究中，我们分析了几种维甲酸对非甾体抗炎药激活基因（NAG-1）在正常人气管支气管上皮细胞（HTBE）和几种肺癌细胞系的表达的影响。维甲酸类化合物6-[3-（1-金刚烷基）-4-羟基苯基]-2-萘甲酸（6-[3-（1-adamantyl）-4-hydroxyphenyl]-2-naphthalicarboxylic acid，AHPN）可显著增强人肺腺癌H460细胞及其它几种癌细胞系中NAG-1 mRNA和蛋白的表达，并呈时间和剂量依赖性。这种诱导对AHPN是特异性的，因为视黄酸、视黄酸受体和类维生素A X受体泛激动剂不能诱导NAG-1，表明这种诱导不是通过类维生素A受体的激活介导的。虽然NAG-1是一个p53应答基因，但AHPN诱导的NAG-1表达并不需要p53。AHPN诱导NAG-1表达至少部分是由于NAG-1 mRNA稳定性增加8倍。与癌细胞相反，NAG-1表达在正常HTBE细胞中被视黄酸和RAR选择性泛激动剂有效诱导，并伴随鳞状分化的抑制和正常分化的启动。在体内，NAG-1的表达，观察到在正常的气管支气管上皮细胞，而没有表达被发现在鳞状化生气管上皮细胞或在人类肺肿瘤的部分。我们的研究结果表明，在正常HTBE和肺癌细胞中，类维生素A对NAG-1表达的诱导受不同机制的调节，并与不同的生物学过程相关。本研究揭示的AHPN治疗与NAG-1表达之间的联系为AHPN的抗肿瘤活性提供了新的机制。
In this study, we analyze the effect of several retinoids on the expression of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in normal human tracheobronchial epithelial (HTBE) cells and several lung carcinoma cell lines. The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) greatly enhances the expression of NAG-1 mRNA and protein in a time- and dose-dependent manner in human lung adenocarcinoma H460 cells and several other carcinoma cell lines. This induction was specific for AHPN because retinoic acid, a retinoic acid receptor-, and a retinoid X receptor pan-agonist were unable to induce NAG-1, suggesting that this induction is not mediated through activation of retinoid receptors. Although NAG-1 is a p53-responsive gene, AHPN-induced NAG-1 expression does not require p53. The induction of NAG-1 expression by AHPN is caused at least in part by an 8-fold increase in the stability of NAG-1 mRNA. In contrast to carcinoma cells, NAG-1 expression is effectively induced by retinoic acid and the RAR-selective pan-agonist in normal HTBE cells and accompanies the inhibition of squamous differentiation and the initiation of normal differentiation. In vivo, NAG-1 expression was observed in the normal tracheobronchial epithelium, whereas no expression was found in either squamous metaplastic tracheal epithelium or in sections of human lung tumors. Our results suggest that the induction of NAG-1 expression by retinoids in normal HTBE and lung carcinoma cells is regulated by distinct mechanisms and is associated with different biological processes. The linkage between AHPN treatment and NAG-1 expression revealed in this study provides a new mechanism for the antitumorigenic activity of AHPN.