Campisi Agata, Bonfanti Roberta, Raciti Giuseppina, Bonaventura Gabriele, Legnani Laura, Magro Gaetano, Pennisi Marzio, Russo Giulia, Chiacchio Maria Assunta, Pappalardo Francesco, Parenti Rosalba
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Institute for Biomedical Research and Innovation (IRIB), Italian National Research Council, Via P. Gaifami 18, 95126 Catania, Italy.
Mol Ther Oncolytics. 2020 Jan 21;16:197-206. doi: 10.1016/j.omto.2020.01.003. eCollection 2020 Mar 27.
Herein, we assess the gene expression changes activated in thyroid tumors through a computational approach, using the MapReduce algorithm. Through this predictive analysis, we identified the TfR1 gene as a critical mediator of thyroid tumor progression. Then, we investigated the effect of TfR1 gene silencing through small interfering RNA (siRNA) in the expression of extracellular signal-regulated kinase 1/2 (Erk1/2) pathway and c-Myc in human differentiated follicular and undifferentiated anaplastic thyroid cancer. The expression levels of cyclin D, p53, and p27, proteins involved in cell cycle progression, were also evaluated. The effect of TfR1 gene silencing through siRNA on the apoptotic pathway activation was also tested. Computational prediction and studies demonstrate that TfR1 plays a key role in thyroid cancer and that its downregulation was able to inhibit the ERK pathway, reducing also c-Myc expression, which blocks the cell cycle and activates the apoptotic pathway. We demonstrate that TfR1 plays a crucial role for a rapid and transient activation of the ERK signaling pathway, which induces a deregulation of genes involved in the aberrant accumulation of intracellular free iron and in drug resistance. We also suggest that TfR1 might represent an important target for thyroid cancer therapy.
在此，我们使用MapReduce算法通过一种计算方法评估甲状腺肿瘤中激活的基因表达变化。通过这种预测性分析，我们确定TfR1基因是甲状腺肿瘤进展的关键调节因子。然后，我们研究了通过小干扰RNA（siRNA）沉默TfR1基因对人分化型滤泡性和未分化间变性甲状腺癌中细胞外信号调节激酶1/2（Erk1/2）通路和c-Myc表达的影响。还评估了细胞周期蛋白D、p53和p27（参与细胞周期进程的蛋白质）的表达水平。还测试了通过siRNA沉默TfR1基因对凋亡通路激活的影响。计算预测和研究表明，TfR1在甲状腺癌中起关键作用，其下调能够抑制ERK通路，同时降低c-Myc表达，从而阻断细胞周期并激活凋亡通路。我们证明，TfR1对于ERK信号通路的快速和短暂激活起着至关重要的作用，ERK信号通路的激活会导致参与细胞内游离铁异常积累和耐药性的基因失调。我们还认为，TfR1可能是甲状腺癌治疗的一个重要靶点。
