Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
J Chin Med Assoc. 2020 Oct;83(10):923-930. doi: 10.1097/JCMA.0000000000000389.
Thyroid tumors are the most frequent neoplasm of the endocrine system. The major treatment is surgical intervention followed by radioiodine therapy. The sodium/iodide symporter (NIS) has positive expression in thyroid carcinomas with good prognoses and plays a critical role in radioiodine therapy response. Low expression of NIS always leads to tumor recurrence or treatment failure. Redifferentiation therapy is more tumor specific than chemotherapy. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists and retinoids are two types of redifferentiating agents. In this study, we examined whether the PPARγ agonist rosiglitazone and retinoid X receptor (RXR) agonist bexarotene could increase NIS expression and exhibit anticancer activity in human thyroid cancer cells.
Using a TCGA data set, we analyzed the expression of NIS (SLC5A5), PPARγ, and RXR in clinical thyroid tumors and assessed their correlations with the relapse-free survival (RFS) of thyroid tumor patients. Moreover, two human thyroid cancer cell lines, differentiated thyroid papillary BCPAP cells and follicular follicular thyroid cancer-131 cells, were treated with different concentrations of the PPARγ agonist rosiglitazone alone or in combination with the RXR agonist bexarotene. Cell growth was analyzed by the MTT assay. NIS protein expression was determined by Western blotting.
From analysis of the TCGA data set, we found that thyroid tumors have lower expression of both NIS (SLC5A5) and PPARγ than nontumor controls. Higher expression levels of NIS, PPARγ, and RXR are associated with higher RFS in patients with thyroid tumors. Moreover, rosiglitazone treatment reduced cell growth and increased NIS protein expression in thyroid cancer cells under normoxic or hypoxic conditions. In addition, bexarotene potentiated the effects of rosiglitazone on cell growth and NIS protein expression.
Our results suggest that the combination of PPARγ and RXR agonists has potential as a chemotherapeutic strategy for thyroid cancer.
甲状腺肿瘤是内分泌系统最常见的肿瘤。主要治疗方法是手术干预，然后进行放射性碘治疗。钠/碘转运体（NIS）在预后良好的甲状腺癌中呈阳性表达，在放射性碘治疗反应中起关键作用。NIS 低表达常导致肿瘤复发或治疗失败。再分化治疗比化疗更具肿瘤特异性。过氧化物酶体增殖物激活受体γ（PPARγ）激动剂和维甲酸是两种再分化剂。在这项研究中，我们研究了 PPARγ 激动剂罗格列酮和维甲酸 X 受体（RXR）激动剂贝沙罗汀是否可以增加 NIS 表达，并在人类甲状腺癌细胞中表现出抗癌活性。
使用 TCGA 数据集，我们分析了临床甲状腺肿瘤中 NIS（SLC5A5）、PPARγ 和 RXR 的表达，并评估了它们与甲状腺肿瘤患者无复发生存率（RFS）的相关性。此外，我们用不同浓度的 PPARγ 激动剂罗格列酮单独或与 RXR 激动剂贝沙罗汀联合处理两种人类甲状腺癌细胞系，分化型甲状腺乳头状 BCPAP 细胞和滤泡状甲状腺癌-131 细胞。用 MTT 法分析细胞生长情况。用 Western blot 法测定 NIS 蛋白表达。
从 TCGA 数据集的分析中，我们发现甲状腺肿瘤的 NIS（SLC5A5）和 PPARγ 表达均低于非肿瘤对照。甲状腺肿瘤患者中 NIS、PPARγ 和 RXR 的表达水平越高，RFS 越高。此外，罗格列酮治疗在常氧或低氧条件下降低甲状腺癌细胞的生长并增加 NIS 蛋白表达。此外，贝沙罗汀增强了罗格列酮对细胞生长和 NIS 蛋白表达的作用。
我们的结果表明，PPARγ 和 RXR 激动剂的联合应用具有作为甲状腺癌化疗策略的潜力。
