Department of Nuclear Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Endocr Relat Cancer. 2023 Jul 25;30(9). doi: 10.1530/ERC-23-0130. Print 2023 Sep 1.
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.
放射性碘治疗是甲状腺乳头状癌 (PTC) 患者的基本治疗方法。钠/碘同向转运体 (NIS) 介导的碘摄取是放射性碘治疗疗效的前提。白细胞介素 6 (IL-6) 是一种促肿瘤细胞因子，但它对 PTC 中 NIS 表达的调节尚未阐明。在这项研究中，我们发现 IL-6 增强了 PTC 细胞的增殖能力。此外，还证明了甲状腺癌组织中 IL-6 与 NIS 表达之间的负相关。IL-6 下调了甲状腺特异性基因，如 NIS、甲状腺过氧化物酶和促甲状腺激素受体，以及甲状腺特异性转录因子，包括甲状腺转录因子-1 (TTF-1) 和配对盒蛋白-8 (PAX-8)。丝裂原活化蛋白激酶和 Janus 激酶抑制剂减轻了 IL-6 对 NIS 表达的抑制作用。c-Jun 或 STAT3 的耗竭也挽救了 IL-6 诱导的 NIS 下调，其中 STAT3 耗竭的作用更强。c-Jun 或 STAT3 的耗竭也恢复了 TTF-1 蛋白的表达。STAT3 的耗竭而不是 c-Jun 的耗竭减轻了 IL-6 对 PAX-8 表达的抑制作用。此外，过表达 TTF-1 和 PAX-8 挽救了 IL-6 对 NIS 的下调。IL-6 受体阻滞剂托珠单抗在 PTC 细胞中没有任何细胞抑制活性，也不能在体外诱导再分化。然而，我们发现该药物阻断了 IL-6 对 NIS 表达的抑制作用。综上所述，IL-6 通过激活丝裂原活化蛋白激酶和 Janus 激酶信号通路抑制 PTC 细胞中的 NIS 转录。
