Interleukin-6 promotes the dedifferentiation of papillary thyroid cancer cells

Abstract

Radioiodine treatment is a fundamental therapy for patients with papillary thyroid cancer (PTC). Sodium/iodide symporter (NIS)-mediated iodine uptake is a prerequisite for the efficacy of radioiodine therapy. Interleukin-6 (IL-6) is a pro-tumor cytokine, but its regulation of NIS expression in PTC has not been elucidated. In this study, we found that IL-6 enhanced the proliferation ability of PTC cells. Moreover, the negative association between IL-6 and NIS expression in thyroid cancer tissues was demonstrated. IL-6 downregulated thyroid-specific genes such as NIS, thyroid peroxidase, and thyroid-stimulating hormone receptor and thyroid-specific transcription factors including thyroid transcription factor-1 (TTF-1) and paired box protein-8 (PAX-8). The inhibitory effects of IL-6 on NIS expression were alleviated by mitogen-activated protein kinase and Janus kinase inhibitors. Depletion of c-Jun or STAT3 also rescued IL-6-induced NIS downregulation, with STAT3 depletion exerting a stronger effect. TTF-1 protein expression was also restored by depleting c-Jun or STAT3. STAT3 depletion, but not c-Jun depletion, alleviated the inhibitory effect of IL-6 on PAX-8 expression. Moreover, the downregulation of NIS by IL-6 was rescued by overexpressing TTF-1 and PAX-8. Tocilizumab, an IL-6 receptor blocker, did not have any cytostatic activity in PTC cells, and it also failed to induce redifferentiation in vitro. However, we found that the drug blocked the inhibitory effect of IL-6 on NIS expression. In summary, IL-6 inhibits NIS transcription in PTC cells by activating mitogen-activated protein kinase and Janus kinase signaling.