Oh Ji Min, Rajendran Ramya Lakshmi, Gangadaran Prakash, Hong Chae Moon, Jeong Ju Hye, Lee Jaetae, Ahn Byeong-Cheol
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
Cancers (Basel). 2022 Mar 31;14(7):1782. doi: 10.3390/cancers14071782.
Radioactive-iodine (RAI) therapy is the mainstay for patients with recurrent and metastatic thyroid cancer. However, many patients exhibit dedifferentiation characteristics along with lack of sodium iodide symporter (NIS) functionality, low expression of thyroid-specific proteins, and poor RAI uptake, leading to poor prognosis. Previous studies have demonstrated the effect of GLI family zinc finger 1 (GLI1) inhibition on tumor growth and apoptosis. In this study, we investigated the role of GLI1 in the context of redifferentiation and improvement in the efficacy of RAI therapy for thyroid cancer. We evaluated GLI1 expression in several thyroid cancer cell lines and selected TPC-1 and SW1736 cell lines showing the high expression of GLI. We performed GLI1 knockdown and evaluated the changes of thyroid-specific proteins expression, RAI uptake and I-131-mediated cytotoxicity. The effect of GANT61 (GLI1 inhibitor) on endogenous NIS expression was also assessed. Endogenous NIS expression upregulated by inhibiting GLI1, in addition, increased expression level in plasma membrane. Also, GLI1 knockdown increased expression of thyroid-specific proteins. Restoration of thyroid-specific proteins increased RAI uptake and I-131-mediated cytotoxic effect. Treatment with GANT61 also increased expression of endogenous NIS. Targeting GLI1 can be a potential strategy with redifferentiation for restoring RAI avidity in dedifferentiated thyroid cancers.
放射性碘（RAI）治疗是复发性和转移性甲状腺癌患者的主要治疗方法。然而，许多患者表现出去分化特征，同时缺乏碘化钠转运体（NIS）功能、甲状腺特异性蛋白表达低以及RAI摄取不良，导致预后不良。先前的研究已经证明了GLI家族锌指蛋白1（GLI1）抑制对肿瘤生长和凋亡的影响。在本研究中，我们研究了GLI1在甲状腺癌再分化和提高RAI治疗疗效方面的作用。我们评估了几种甲状腺癌细胞系中GLI1的表达，并选择了显示GLI高表达的TPC-1和SW1736细胞系。我们进行了GLI1基因敲低，并评估了甲状腺特异性蛋白表达、RAI摄取和I-131介导的细胞毒性的变化。还评估了GLI1抑制剂GANT61对内源性NIS表达的影响。抑制GLI1可上调内源性NIS表达，此外，还可增加其在质膜中的表达水平。此外，GLI1基因敲低可增加甲状腺特异性蛋白的表达。甲状腺特异性蛋白的恢复增加了RAI摄取和I-131介导的细胞毒性作用。用GANT61治疗也增加了内源性NIS的表达。靶向GLI1可能是一种使去分化甲状腺癌再分化以恢复RAI亲和力的潜在策略。
