Tracey Lorraine, Villuendas Raquel, Ortiz Pablo, Dopazo Ana, Spiteri Inmaculada, Lombardia Luis, Rodríguez-Peralto Jose L, Fernández-Herrera Jesús, Hernández Almudena, Fraga Javier, Dominguez Orlando, Herrero Javier, Alonso Miguel A, Dopazo Joaquin, Piris Miguel A
Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
Am J Pathol. 2002 Nov;161(5):1825-37. doi: 10.1016/s0002-9440(10)64459-8.
Interferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction.
α干扰素疗法已被证明在蕈样肉芽肿的治疗中具有活性，尽管个体对该疗法的反应不可预测，且基本上取决于未知因素。为了更好地理解α干扰素耐药的分子机制，我们从一个敏感的皮肤T细胞淋巴瘤细胞系中培育出了一个α干扰素耐药变体。我们使用包含6386个与癌症相关基因的cDNA微阵列进行了表达分析，以检测两个变体之间差异表达的基因。实验表明，对α干扰素的耐药性始终与一组39个基因的表达变化相关，这些基因涉及信号转导、细胞凋亡、转录调控和细胞生长。进一步的研究证实，两个变体之间STAT1和STAT3的表达以及α干扰素的诱导和激活没有改变。耐药细胞高度过表达的MAL基因，在一系列接受α干扰素和/或光化学疗法治疗的皮肤T细胞淋巴瘤患者的肿瘤细胞中也有表达。MAL表达与完全缓解时间延长相关。敏感细胞和耐药细胞的时间进程实验显示，参与干扰素反应（1至4小时）、细胞生长和细胞凋亡（24至48小时）以及信号转导的一组基因存在差异表达。
