Ramos-Nino Maria E, Scapoli Luca, Martinelli Marcella, Land Susan, Mossman Brooke T
Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
Cancer Res. 2003 Jul 1;63(13):3539-45.
Malignant mesothelioma is a cancer with poor prognosis associated with exposures to asbestos. The mechanisms of asbestos-induced mesotheliomas are unclear, and studies are required to find diagnostic tools and therapies to improve the survival rates of patients. After oligonucleotide microarray analysis (Affymetrix array) of normal rat pleural mesothelial (RPM) cells, RPM cells exposed to crocidolite asbestos, and rat mesotheliomas, subsets of genes that changed in expression were categorized, including the highly up-regulated, early response proto-oncogene, fra-1. Increases in fra-1 in both rat and human mesotheliomas and a subset of genes common to both asbestos-exposed RPM cells and mesotheliomas that mimicked fra-1 patterns of expression were subsequently confirmed using real-time quantitative PCR. Using RNA interference technology, fra-1 gene silenced RPM cells were assayed by real-time quantitative PCR for the expression of possible fra-1-regulated genes. Results reveal that induction of cd44 and c-met is causally linked to fra-1 expression, connecting fra-1 with genes governing cell motility and invasion in mesothelioma. These studies suggest that inhibition of fra-1 signaling pathways may be a strategy for therapy of malignant mesothelioma.
恶性间皮瘤是一种预后较差的癌症，与接触石棉有关。石棉诱发间皮瘤的机制尚不清楚，需要开展研究以找到诊断工具和治疗方法来提高患者的生存率。在对正常大鼠胸膜间皮（RPM）细胞、接触青石棉的RPM细胞和大鼠间皮瘤进行寡核苷酸微阵列分析（Affymetrix阵列）后，对表达发生变化的基因子集进行了分类，其中包括高度上调的早期反应原癌基因fra-1。随后使用实时定量PCR证实了大鼠和人间皮瘤中fra-1的增加，以及接触石棉的RPM细胞和间皮瘤共有的一部分基因，这些基因模仿了fra-1的表达模式。使用RNA干扰技术，通过实时定量PCR检测fra-1基因沉默的RPM细胞中可能受fra-1调控的基因的表达。结果显示，cd44和c-met的诱导与fra-1的表达存在因果关系，将fra-1与间皮瘤中控制细胞运动和侵袭的基因联系起来。这些研究表明，抑制fra-1信号通路可能是治疗恶性间皮瘤的一种策略。
