GENE SILENCING OF TRANSFERRIN-1 RECEPTOR AS A POTENTIAL THERAPEUTICAL TARGET FOR HUMAN FOLLICULAR AND ANAPLASTIC THYROID CANCER

Abstract Herein, we assessed the gene expression changes activated in thyroid tumors through a computational approach, using 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 siRNA in the expression of Erk1/2 pathway and c-Myc in human differentiated follicular and undifferentiated anaplastic thyroid cancer. The expression levels of cyclin D1, 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 tested, too. Computational prediction and in vitro studies demonstrate that TfR1 plays a key role in thyroid cancer and that its down-regulation was able to inhibit 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.