碘对体外培养哺乳期乳腺细胞钠碘转运体表达的作用及肿瘤坏死因子α对其的影响

目的 观察不同碘营养水平时体外培养哺乳期乳腺细胞钠碘转运体(NIS)表达水平,以及肿瘤坏死因子α(TNF-α)对其的影响作用.方法 体外培养小鼠原代哺乳期乳腺细胞,分为低碘1组、低碘2组、适碘组、高碘1组、高碘2组,分别加入含碘0、5、50、3000、10 000μg/L的DEME/F12培养液培养24 h,然后部分换成含对应剂量的碘加TNF-α(10-2 mg/L)的DEME/F12培养液,继续培养24 h.用实时荧光定量PCR方法检测哺乳期乳腺细胞NIS mRNA表达水平,并用In-Cell Western方法检测NIS蛋白表达水平.结果 单纯加碘时低碘1组[(64.66±14.99)×10-4]乳腺细胞NIS mRNA表达水平高于适碘组[(22.76±7.36)×10-4,P＜0.05],高碘1组[(10.18±3.53)×10-4]、高碘2组[(8.59±2.89)×10-4]低于适碘组(P均＜0.05);随着碘剂量升高,乳腺细胞NIS mRNA表达水平呈下降趋势.在碘加TNF-α时,低碘1组、低碘2组、适碘组[(2.72±0.45)、(2.69±0.68)、(1.80±0.67)×10-4]乳腺细胞NIS mRNA表达水平低于单纯加碘时对应各组[(64.66±14.99)、(29.82±4.47)、(22.76±7.36)×10-4,P均＜0.05];高碘1组[(6.58±2.87)×10-4]、高碘2组[(7.04±.1.36)×10-4]高于适碘组(P均＜0.05);随着碘缺乏和碘过量程度加重,乳腺细胞NIS mRNA表达水平呈上升趋势.随着碘剂量升高,单纯加碘时乳腺细胞NIS蛋白表达水平呈下降趋势.碘加TNF-α时各组乳腺细胞NIS蛋白表达水平与单纯加碘时对应各组比较有降低的趋势.碘加TNF-α时,随着碘缺乏和碘过量程度加重,乳腺细胞NIS蛋白表达水平均呈上升趋势.结论 随着碘剂量升高,哺乳期乳腺细胞NIS mRNA和蛋白表达水平均呈下降趋势.TNF-α对不同碘营养水平下哺乳期乳腺细胞NIS mRNA和蛋白表达具有抑制作用.     

碘对哺乳期大鼠甲状腺和乳腺钠碘转运体、胰岛素样生长因子Ⅰ及转化生长因子βmRNA表达的影响

目的 观察碘对哺乳期大鼠甲状腺和乳腺钠碘转运体(NIS)、胰岛素样生长因子Ⅰ(IGF-Ⅰ)、转化生长因子β (TGF-β)mRNA表达的影响,探讨NIS、IGF-Ⅰ 、TGF-β mRNA在哺乳期大鼠甲状腺和乳腺摄碘中的作用.方法 选择Wistar大鼠101只,其中雌性80只,雄性21只,体质量80- 100g.按体质量将雌性大鼠随机分为5组:对照组(正常饲料、饮含碘50μg/L去离子水),低碘1组、2组(低碘饲料,分别饮用去离子水、含碘5 μg/L去离子水),高碘1组、2组(正常饲料,分别饮用含碘3000、10 000 μg/L去离子水),每组16只.在喂养3个月后,将雌鼠与雄鼠按3∶1合笼交配,在产后第5、10天,分别处死各组雌鼠,取甲状腺和乳腺,采用实时荧光定量PCR检测哺乳期大鼠甲状腺和乳腺NIS、IGF-Ⅰ 、TGF-β mRNA表达.结果 产后第5天,哺乳期大鼠甲状腺和乳腺的NIS、IGF-Ⅰ 、TGF-β mRNA表达组间比较差异均有统计学意义(NIS:F值分别为631.46、64.91,P均＜0.01;IGF-Ⅰ:F值分别为11.45、6.56,P均＜0.01;TGF-β:F值分别为291.83、304.53,P均＜0.01).与对照组大鼠甲状腺和乳腺NIS、IGF-Ⅰ 、TGF-β mRNA[NIS:0.0066±0.0023、(0.1481±0.0711)×10-2;IGF-Ⅰ:0.0419±0.0062、0.0542±0.0044;TGF:0.1416±0.0277、0.1670±0.0499]比较,低碘1组[NIS:0.0447±0.0110、(0.3030±0.1831)× 10-2;IGF-Ⅰ:0.0662±0.0078、0.0902±0.008;TGF-β:0.5514±0.0508、0.6942±0.0367]、2组[NIS:0.0317±0.0081 、(0.3017±0.1601)×10-2;IGF-Ⅰ:0.0645±0.0054、0.0894±0.0093;TGF-β:0.5292±0.0332、0.6704±0.0277]表达明显升高(P均＜0.01);高碘1组NIS mRNA[0.0043±0.0011、(0.1233±0.0954)×10-2]、2组NIS mRNA[0.0037 ±0.0017、(0.1058±0.0854)×10-2]表达降低(P均＜0.05),但IGF-Ⅰ [0.0521±0.0910、0.0715±0.0026;0.0516±0.0078、0.0697±0.0038] 、TGF-β mRNA[0.2087±0.0425、0.2361±0.0425;0.1971±0.0237、0.2257±0.0752]表达升高(P均＜0.05).产后第10天,哺乳期大鼠甲状腺和乳腺的NIS、IGF-Ⅰ 、TGF-β mRNA表达组间比较差异均有统计学意义(NIS:F值分别为103.55、116.32,P均＜ 0.01;IGF-Ⅰ:F值分别为67.67、11.98,P均＜0.01;TGF-β:F值分别为74.30、381.30,P均＜0.01).与对照组大鼠甲状腺和乳腺NIS、IGF-Ⅰ 、TGF-β mRNA[NIS:0.0069±0.0011 、(0.1337±0.0599)× 10-2;IGF-Ⅰ:0.0390±0.0071、0.0534±0.0056;TGF-β:0.1351±0.0336、0.1534±0.0320]比较,低碘1组[NIS:0.0432±0.0165、(0.2962±0.0985)× 10-2;IGF- Ⅰ:0.0643±0.0088、0.0873±0.0055;TGF-β:0.5042±0.0912、0.6408±0.0420]、2组[NIS:0.0287±0.0111、(0.2873±0.0862)×10-2;IGF-Ⅰ:0.0621±0.0094、0.0862±0.0038;TGF-β:0.4893±0.0504、0.6372±0.0389]表达明显升高(P均＜0.01);高碘1组NIS mRNA [0.0042±0.0029、(0.1006±0.0909)× 10-2]、2组NIS mRNA [0.0035±0.0020、(0.0890±0.0119)×10-2]表达降低(P均＜0.01),但IGF-Ⅰ [0.0516±0.0078、0.0668±0.0071;0.0508±0.0089、0.0621±0.0064] 、TGF-β mRNA [0.2007±0.0546、0.2175±0.0370;0.1959±0.0393、0.2097±0.0425]表达升高(P均＜0.05).各组大鼠产后第5天与第10天比较,无论是甲状腺还是乳腺,NIS、IGF-Ⅰ 、TGF-β mRNA表达差异无统计学意义(P均＞0.05).结论 哺乳期大鼠甲状腺和乳腺对碘存在调控机制,低碘时甲状腺和乳腺NIS 、IGF-Ⅰ 、TGF-β mRNA表达增多,摄碘能力增强,满足机体的需要;高碘时甲状腺和乳腺NIS mRNA表达减少,由于摄碘能力降低,碘的摄入减少,减轻了高碘对仔鼠的危害.     

不同碘营养水平对哺乳期大鼠甲状腺和乳腺钠碘转运体mRNA表达的影响

目的 观察不同碘营养水平对哺乳期大鼠甲状腺和乳腺钠碘转运体(NIS)mRNA表达水平的影响.方法 Wistar大鼠30只,体质量40～60 g.按体质量将大鼠随机分成3组:低碘组(去离子水),适碘组(含碘150 μg/L的去离子水),高碘组(含碘3000μg/L的去离子水),3组均喂合成饲料.喂养3个月后,与雄鼠合笼交配,待母鼠哺乳5 d后处死,取母鼠乳腺、甲状腺及血清.采用温和酸消化法测定血清碘,放射免疫分析法测定血清T_3、T_4水平,实时荧光定量PCR法检测乳腺和甲状腺NIS mRNA表达.结果 哺乳期大鼠血清碘、T_3、T_4、NIS mRNA表达,组间比较差异有统计学意义(F值分别为499.94、16.67、8.49,H=7.58,P均<0.05).血清碘适碘组[(43.42±692)μg/L]高于低碘组[(17.38±3.27)μg/L,P<0.05],高碘组[(350.10±38.46)μg/L]高于适碘组(P<0.05).血清T_3水平,低碘组、高碘组[(1.11±0.25)、(1.61±0.33)μg/L]低于适碘组[(2.18±0.46)μg/L,P均<0.05].血清T_4水平,低碘组[(33.40±11.11)μg/L]低于高碘组[(56.54±10.38)μg/L,P<0.05].甲状腺NIS mRNA表达水平低碘组(0.280±0.030)高于适碘组(0.240±0.030,P<0.05).高碘组(0.069±0.037)低于适碘组(P<0.05).哺乳期乳腺NIS mRNA表达水平高碘组(0.027±0.007)低于适碘组(0.051±0.019,P<0.05).结论 轻度低碘能够提高甲状腺NIS mRNA表达,保护母体免受低碘的危害,但对下一代的保护作用不明显或没有保护作用;高碘抑制甲状腺和乳腺NIS mRNA表达,保护母体及下一代免受高碘的危害.     

钠/碘转运体

钠/碘转运体(NIS)是位于甲状腺细胞基底膜上的一类膜抗原,在甲状腺对碘的主动转运过程中发挥重要作用.此蛋白受甲状腺刺激素(TSH)、碘、细胞因子和生长因子等多种因素的广泛调节.自身免疫性甲状腺疾病时NIS的表达发生了明显变化,患者体内出现抗NIS自身抗体.此外,NIS还与甲状腺冷结节和先天性甲减等甲状腺疾病的发病机理密切相关.采用NIS转基因对甲状腺癌的放射性碘治疗具有重要的临床价值.     

钠/碘共转运体单克隆抗体的制备与应用

钠/碘共转运体(NIS)是甲状腺滤泡细胞膜上的一类特殊糖蛋白,具有摄取并浓集碘的功能.利用杂交瘤技术经过动物免疫、细胞融合、筛选阳性克隆、亚克隆制备鼠抗人NIS单克隆抗体,并用酶联免疫吸附分析法、Western印迹等方法鉴定其特异性.NIS单克隆抗体为NIS抗原-抗体的研究提供了新的工具,它不仅可以用于甲状腺、乳腺等领域的基础研究,而且可以用于临床,为甲状腺疾病的诊断和治疗提供切实保障.     

碘过量对哺乳期母鼠乳腺钠碘转运体mRNA和蛋白表达的影响

目的 观察碘过量对哺乳期母鼠乳腺钠碘转运体(sodium-iodide symporter,NIS)mRNA及蛋白表达的影响.方法 断乳1个月健康Wistar大鼠60只,雌雄比为2:1.将大鼠按体质量随机分为适碘组(30只)、10倍碘组(15只)、100倍碘组(15只),通过饮食(含碘300μg/ks)和饮水(含碘5、1845、20 295μg/L)摄碘.喂养3个月后交配产仔鼠,在哺乳第10天,采用砷铈催化分光光度法测定母鼠尿碘和乳汁碘.取母鼠乳腺,用反转录聚合酶链反应(RT-PCR)测定NIS mRNA表达;用SABC法进行免疫组化染色观察NIS蛋白表达强度.结果 ①母鼠尿碘:适碘组344.7μg/L、10倍碘组3597.5μg/L、100倍碘组25 404.3μg/L,10倍碘组和100倍碘组分别是适碘组的10.4倍和73.7倍.②母鼠乳汁碘:适碘组6.0×103μg/L、10倍碘组27.1×103μg/L、100倍碘组191.0×103μg/L,10倍碘组和100倍碘组分别是适碘组的4.5倍和31.8倍,母鼠乳汁碘增加倍数低于尿碘.③母鼠乳腺NIS表达:NIS raRNA表达组间比较差异有统计学意义(F=24.19,P＜0.01);其中适碘组(1.532±0.044)较10倍碘组(1.250±0.034)、100倍碘组(1.272±0.039)明显增高(P＜0.01),而且哺乳期母鼠乳腺N1S mRNA表达(1.532±0.044)高于非哺乳期母鼠(0.879±0.018),二者比较差异有统计学意义(t=19.09,P＜0.01);母鼠乳腺NIS蛋白表达强度随碘摄入量增加而减弱.结论 过量碘摄入可抑制乳腺NISmRNA和蛋白表达,限制乳汁中的含碘量随碘摄入量增加的幅度,此机制对下一代有着重要的保护作用.     

不同碘负荷对小鼠甲状腺钠碘转运体基因表达的影响

目的 旨在探讨不同碘负荷状态下钠碘转运体(NIS)基因表达的变化及其在甲状腺自身调节中的作用.方法 取断乳1月龄的Babl/c小鼠按碘摄入量不同分为低碘绀、正常碘组、5倍碘组、10倍碘组和50倍碘组,饲养3个月、6个月后处死动物.采用实时荧光定量PCR和免疫组化检测NIS mRNA和蛋白表达水平,采用过硫酸铵消化砷-铈催化分光光度法测定甲状腺组织碘含量,采用竞争结合放射免疫分析方法检测甲状腺组织激素水平.结果 与正常碘组比较.各月龄低碘组小鼠NIS mRNA和蛋白表达显著上调,NIS主要定位于细胞膜.具有运碘功能,甲状腺摄碘功能增强,但长期严重碘缺乏最终导致甲状腺组织中碘含量和甲状腺组织激素水平明显降低;各高碘组NIS mRNA和蛋白表达有所下降,呈现随碘摄入量增加表达逐渐减低的趋势,且NIS主要分布于胞浆内,不具备跨膜转运碘的能力.甲状腺摄碘能力显著下降,甲状腺组织中碘含量虽有所升高,但小与碘摄人成平行关系.结论 不同碘负荷状态下 NIS基因表达的调控可发生在转录、翻译和翻译后水平,NIS基因表达及其活性的调节是机体适应低碘、耐受高碘的一种重要保护机制,是甲状腺自身调节的关键所在.     

不同碘负荷对小鼠甲状腺钠碘转运体基因表达的影响

目的 旨在探讨不同碘负荷状态下钠碘转运体(NIS)基因表达的变化及其在甲状腺自身调节中的作用.方法 取断乳1月龄的Babl/c小鼠按碘摄入量不同分为低碘绀、正常碘组、5倍碘组、10倍碘组和50倍碘组,饲养3个月、6个月后处死动物.采用实时荧光定量PCR和免疫组化检测NIS mRNA和蛋白表达水平,采用过硫酸铵消化砷-铈催化分光光度法测定甲状腺组织碘含量,采用竞争结合放射免疫分析方法检测甲状腺组织激素水平.结果 与正常碘组比较.各月龄低碘组小鼠NIS mRNA和蛋白表达显著上调,NIS主要定位于细胞膜.具有运碘功能,甲状腺摄碘功能增强,但长期严重碘缺乏最终导致甲状腺组织中碘含量和甲状腺组织激素水平明显降低;各高碘组NIS mRNA和蛋白表达有所下降,呈现随碘摄入量增加表达逐渐减低的趋势,且NIS主要分布于胞浆内,不具备跨膜转运碘的能力.甲状腺摄碘能力显著下降,甲状腺组织中碘含量虽有所升高,但小与碘摄人成平行关系.结论 不同碘负荷状态下 NIS基因表达的调控可发生在转录、翻译和翻译后水平,NIS基因表达及其活性的调节是机体适应低碘、耐受高碘的一种重要保护机制,是甲状腺自身调节的关键所在.     

不同碘负荷对小鼠甲状腺钠碘转运体基因表达的影响

目的 旨在探讨不同碘负荷状态下钠碘转运体(NIS)基因表达的变化及其在甲状腺自身调节中的作用.方法 取断乳1月龄的Babl/c小鼠按碘摄入量不同分为低碘绀、正常碘组、5倍碘组、10倍碘组和50倍碘组,饲养3个月、6个月后处死动物.采用实时荧光定量PCR和免疫组化检测NIS mRNA和蛋白表达水平,采用过硫酸铵消化砷-铈催化分光光度法测定甲状腺组织碘含量,采用竞争结合放射免疫分析方法检测甲状腺组织激素水平.结果 与正常碘组比较.各月龄低碘组小鼠NIS mRNA和蛋白表达显著上调,NIS主要定位于细胞膜.具有运碘功能,甲状腺摄碘功能增强,但长期严重碘缺乏最终导致甲状腺组织中碘含量和甲状腺组织激素水平明显降低;各高碘组NIS mRNA和蛋白表达有所下降,呈现随碘摄入量增加表达逐渐减低的趋势,且NIS主要分布于胞浆内,不具备跨膜转运碘的能力.甲状腺摄碘能力显著下降,甲状腺组织中碘含量虽有所升高,但小与碘摄人成平行关系.结论 不同碘负荷状态下 NIS基因表达的调控可发生在转录、翻译和翻译后水平,NIS基因表达及其活性的调节是机体适应低碘、耐受高碘的一种重要保护机制,是甲状腺自身调节的关键所在.     

不同碘负荷对小鼠甲状腺钠碘转运体基因表达的影响

目的 旨在探讨不同碘负荷状态下钠碘转运体(NIS)基因表达的变化及其在甲状腺自身调节中的作用.方法 取断乳1月龄的Babl/c小鼠按碘摄入量不同分为低碘绀、正常碘组、5倍碘组、10倍碘组和50倍碘组,饲养3个月、6个月后处死动物.采用实时荧光定量PCR和免疫组化检测NIS mRNA和蛋白表达水平,采用过硫酸铵消化砷-铈催化分光光度法测定甲状腺组织碘含量,采用竞争结合放射免疫分析方法检测甲状腺组织激素水平.结果 与正常碘组比较.各月龄低碘组小鼠NIS mRNA和蛋白表达显著上调,NIS主要定位于细胞膜.具有运碘功能,甲状腺摄碘功能增强,但长期严重碘缺乏最终导致甲状腺组织中碘含量和甲状腺组织激素水平明显降低;各高碘组NIS mRNA和蛋白表达有所下降,呈现随碘摄入量增加表达逐渐减低的趋势,且NIS主要分布于胞浆内,不具备跨膜转运碘的能力.甲状腺摄碘能力显著下降,甲状腺组织中碘含量虽有所升高,但小与碘摄人成平行关系.结论 不同碘负荷状态下 NIS基因表达的调控可发生在转录、翻译和翻译后水平,NIS基因表达及其活性的调节是机体适应低碘、耐受高碘的一种重要保护机制,是甲状腺自身调节的关键所在.     

Enhancement of sodium/iodide symporter expression in thyroid and breast cancer

The sodium/iodide symporter (NIS) mediates iodide uptake in the thyroid gland and lactating breast. NIS mRNA and protein expression are detected in most thyroid cancer specimens, although functional iodide uptake is usually reduced resulting in the characteristic finding of a 'cold' or non-functioning lesion on a radioiodine image. Iodide uptake after thyroid stimulating hormone (TSH) stimulation, however, is sufficient in most differentiated thyroid cancer to utilize beta-emitting radioactive iodide for the treatment of residual and metastatic disease. Elevated serum TSH, achieved by thyroid hormone withdrawal in athyreotic patients or after recombinant human thyrotropin administration, directly stimulates NIS gene expression and/or NIS trafficking to the plasma membrane, increasing radioiodide uptake. Approximately 10-20% differentiated thyroid cancers, however, do not express the NIS gene despite TSH stimulation. These tumors are generally associated with a poor prognosis. Reduced NIS gene expression in thyroid cancer is likely due in part, to impaired trans-activation at the proximal promoter and/or the upstream enhancer. Basal NIS gene expression is detected in about 80% breast cancer specimens, but the fraction with functional iodide transport is relatively low. Lactogenic hormones and various nuclear hormone receptor ligands increase iodide uptake in breast cancer cells in vitro, but TSH has no effect. A wide range of 'differentiation' agents have been utilized to stimulate NIS expression in thyroid and breast cancer using in vitro and in vivo models, and a few have been used in clinical studies. Retinoic acid has been used to stimulate NIS expression in both thyroid and breast cancer. There are similarities and differences in NIS gene regulation and expression in thyroid and breast cancer. The various agents used to enhance NIS expression in thyroid and breast cancer will be reviewed with a focus on the mechanism of action. Agents that promote tumor differentiation, or directly stimulate NIS gene expression, may result in iodine concentration in 'scan-negative' thyroid cancer and some breast cancer.     

KT5823 differentially modulates sodium iodide symporter expression, activity, and glycosylation between thyroid and breast cancer cells

Na(+)/I(-) symporter (NIS)-mediated iodide uptake into thyroid follicular cells serves as the basis of radioiodine therapy for thyroid cancer. NIS protein is also expressed in the majority of breast tumors, raising potential for radionuclide therapy of breast cancer. KT5823, a staurosporine-related protein kinase inhibitor, has been shown to increase thyroid-stimulating hormone-induced NIS expression, and thus iodide uptake, in thyroid cells. In this study, we found that KT5823 does not increase but decreases iodide uptake within 0.5 h of treatment in trans-retinoic acid and hydrocortisone-treated MCF-7 breast cancer cells. Moreover, KT5823 accumulates hypoglycosylated NIS, and this effect is much more evident in breast cancer cells than thyroid cells. The hypoglycosylated NIS is core glycosylated, has not been processed through the Golgi apparatus, but is capable of trafficking to the cell surface. KT5823 impedes complex NIS glycosylation at a regulatory point similar to brefeldin A along the N-linked glycosylation pathway, rather than targeting a specific N-glycosylated site of NIS. KT5823-mediated effects on NIS activity and glycosylation are also observed in other breast cancer cells as well as human embryonic kidney cells expressing exogenous NIS. Taken together, KT5823 will serve as a valuable pharmacological reagent to uncover mechanisms underlying differential NIS regulation between thyroid and breast cancer cells at multiple levels.     

A perspective view of sodium iodide symporter research and its clinical implications

The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues, in particular the lactating mammary gland. Cloning and molecular characterization of the NIS have allowed the investigation of its key role in thyroid physiology as well as its potential pathophysiological and therapeutic implications in benign and malignant thyroid diseases. Similarly, elucidating the mechanisms underlying the regulation of NIS in lactating mammary gland and breast cancer, in which more than 80% of cases express endogenous NIS, may lead to findings that have novel implications for pathophysiology and therapy. Two approaches may, in the future, pave the way to extend the use of radioiodide treatment to nonthyroidal cancer. One is based on the reinduction of endogenous NIS expression in thyroid and breast cancer by targeting the main mechanisms involving tumoral transformation and dedifferentiation. The other is based on the application of NIS as a novel cytoreductive gene therapy strategy. NIS offers the unique advantage that it can be used both as a reporter and as a therapeutic gene, so that it is possible to image, monitor, and treat the tumor with radioiodide, just as in differentiated thyroid cancer. This review summarizes the main recent findings in NIS research that have a direct impact on diagnosis and therapeutic management.     

Rapid communication: predominant intracellular overexpression of the Na(+)/I(-) symporter (NIS) in a large sampling of thyroid cancer cases

Here we report the analysis of the Na(+)/I(-) symporter (NIS) protein expression in 57 thyroid cancer samples by immunohistochemistry with high-affinity anti-NIS Abs. As many as 70% of these samples exhibited increased NIS expression with respect to the normal surrounding thyroid tissue. Most significantly, NIS was located in these samples either in both the plasma membrane and intracellular compartments simultaneously, or exclusively in intracellular compartments. This suggests that NIS is clearly expressed or even overexpressed in most thyroid cancer cells, but malignant transformation in some of these cells interferes either with the proper targeting of NIS to the plasma membrane, or with the mechanisms that retain NIS in the plasma membrane after it has been targeted. The results further indicate that, in addition to indicating NIS expression in cases where it is absent (approximately 30%), improvements in (131)I radioablation therapy might result from promoting targeting of NIS to the plasma membrane in the majority (approximately 70%) of thyroid cancers.     

Rarity of anti- Na+/I- symporter (NIS) antibody with iodide uptake inhibiting activity in autoimmune thyroid diseases (AITD)

The search for antibody against the Na+/I- symporter (NIS) has seen conflicting results over the years. Prior to cloning of NIS, Raspe et al found iodide uptake inhibiting sera were rare in autoimmune thyroid diseases (AITD) while post-cloning, others reported the presence of antibody in 12-15% of Hashimoto's thyroiditis (HT) and 30-84% of Graves' disease (GD). To evaluate the role of NIS as a potential antigen in AITD, a stable COS 7 cell line expressing high level of functional hNIS was established which allowed the screening of large number of sera for iodide uptake inhibiting activity in a 96-well plate format. Five hundred and fourteen serum samples taken from normal subjects and patients with AITD, non-autoimmune thyroid diseases, and non-thyroid autoimmune diseases were assayed for presence of iodide uptake inhibiting activity. Under the influence of these sera, iodide uptake showed a normal frequency distribution and diminution of uptake 2 SDs below the mean of controls was observed with 14 sera. Among these, 7 that were available for further study were re-evaluated after dialysis and/or Ig G extraction. All 7 sera lost their iodide uptake inhibiting activity, indicating that the effects were not antibody mediated and unknown serum factors had been responsible. In conclusion, contrary to previous results, the present study indicates that antibodies capable of modulating NIS activity are rare in AITD.     

Signaling through 3',5'-cyclic adenosine monophosphate and phosphoinositide-3 kinase induces sodium/iodide symporter expression in breast cancer

The sodium/iodide symporter (NIS) is a membrane transport glycoprotein normally expressed in the thyroid gland and lactating mammary gland. NIS is a target for radioiodide imaging and therapeutic ablation of thyroid carcinomas and has the potential for similar use in breast cancer treatment. To facilitate NIS-mediated radionuclide therapy, it is necessary to identify signaling pathways that lead to increased NIS expression and function in breast cancer. We examined NIS expression in mammary tumors of 14 genetically engineered mouse models to identify genetic manipulations associated with NIS induction. The cAMP and phosphoinositide-3 kinase (PI3K) signaling pathways are associated with NIS up-regulation. We showed that activation of PI3K alone is sufficient to increase NIS expression and radioiodide uptake in MCF-7 human breast cancer cells, whereas cAMP stimulation increases NIS promoter activity and NIS mRNA levels but is not sufficient to increase radioiodide uptake. This study is the first to demonstrate that NIS expression is induced by cAMP and/or PI3K in breast cancer both in vivo and in vitro.