Gene Silencing of Transferrin-1 Receptor as a Potential Therapeutic Target for Human Follicular and Anaplastic Thyroid Cancer
Gene Silencing of Transferrin-1 Receptor as a Potential Therapeutic Target for Human Follicular and Anaplastic Thyroid Cancer
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DOI：
10.1016/j.omto.2020.01.003
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发表时间：
2020-03-27
影响因子：
5.7
通讯作者：
Parenti, Rosalba
中科院分区：
文献类型：
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作者：
Campisi, Agata;Bonfanti, Roberta;Parenti, Rosalba
在这里，我们通过一种计算方法，使用MapReduce算法来评估甲状腺肿瘤中激活的基因表达变化。通过这一预测性分析，我们确定TfR1基因是甲状腺肿瘤进展的关键介质。然后，我们研究了小干扰RNA(SiRNA)沉默TfR1基因对人分化滤泡性甲状腺癌和未分化间变性甲状腺癌细胞外信号调节蛋白1/2(ERK1/2)通路和c-Myc表达的影响。检测细胞周期相关蛋白Cyclin D-1、P53和p27的表达水平。同时检测了通过siRNA沉默TfR1基因对细胞凋亡途径激活的影响。计算预测和体外研究表明，TfR1在甲状腺癌中起关键作用，它的下调能够抑制ERK通路，减少c-Myc的表达，从而阻断细胞周期并激活凋亡途径。我们证明，TfR1在ERK信号通路的快速和瞬时激活中起着关键作用，该信号通路导致参与细胞内游离铁异常积累和耐药的基因的解除调控。我们还认为TfR1可能是甲状腺癌治疗的一个重要靶点。
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-1, 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 in vitro 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.