Abstract
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Objectives Despite an overall relatively good prognosis, patients with recurrent or metastatic thyroid cancer are not rare. Thyroid cancer stem cell is a thyroid cancer cell population capable of self-renewal and is redioresistant. This population survives I-131 therapy and contributes to tumor recurrence and metastasis and is considered to be the target for further development of therapeutic strategy. Several chemodrugs or agents were demonstrate to induce re-expression of thyroid cancer specific genes, such as NIS or Tg. However, these agents may also enrich the thyroid cancer stem cell population due to their chemoresistance. EGFR/PI3K and EGFR/MEK pathways are reported to regulate cancer cell proliferation and survival. In this study, 3 inhibitors including gefitinib (EGFR), LY294002 (PI3K) and PD98059 (MEK) were tested for the ability to induce differentiation and inhibit self-renewal of ARO anaplastic thyroid cancer cell.
Methods After treatment of gefitinib, LY294002 and PD98059, separately, ARO cells were subjected to mRNA expression analysis, I-131 uptake and tumor sphere forming assay.
Results Cells treated with LY294002 and PD98059 showed upregulation of NIS, Tg and TPO genes. Gefitinib had no effect on these genes. Treatment of LY294002 and PD98059, but not gefitinib increased the I-131 uptake. Only LY294002 successfully downregulated the expression of Oct4 and nanog genes. LY294002 significantly attenuated tumor sphere-forming ability but PD98059 did not.
Conclusions PI3K inhibitor LY294002 may induce differentiation of anaplastic thyroid cancer and attenuates self-renewal of cancer stem cells. The results suggest that PI3K inhibitor is a potential candidate for targeting thyroid cancer stem cells as well as improving the effect of radioiodide therapy for anaplastic thyroid cancer.