甲状腺细胞周期和增生的控制
在正常成人中，甲状腺的重量及其组成成分相对恒定。人甲状腺细胞一般每5～10年进行一次细胞循环，即人的一生中有6～8次细胞更新。细胞的生长调控最终发生在细胞周期水平，在这一过程中，细胞周期调控蛋白起着关键作用，对预防和延缓疾病的进展具有重要意义。
1.正常人甲状腺细胞中促有丝分裂模式：胰岛素和IGF-1对人体很多细胞都具有促进生长分化的作用，是TSH对人甲状腺的共同促有丝分裂因子。它们通过多种机制发挥促有丝分裂作用：①胰岛素和IGF-1直接诱导细胞分裂而使细胞数量增加。②胰岛素和IGF-1对TSH的“允许作用”。在没有胰岛素存在时，TSH对甲状腺细胞没有促生长作用，胰岛素和TSH通过cAMP调节细胞生长和DNA合成。胰岛素和IGF-1对TSH的作用包括：细胞数量的增加和特异性蛋白质细胞周期素（Cyclin）D3，Cyclin D1 和Cyclin依赖蛋白激酶（Cyclin-Dependent Kinase，CDK）的合成、抑制甲状腺转录因子1（TTF1）基因的表达；研究发现胰岛素对磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（PKB）途径有很强的激活作用[26-35]。③TSH可以通过升高cAMP诱导甲状腺细胞IGF-1R和胰岛素受体的表达，从而起到协同和增强胰岛素及IGF-1的作用。
2.蛋白激酶级联：TSH可以在几分钟内引起蛋白磷酸化，这种作用是由佛波醇和cAMP类似物引起的。EGF、HGF以及佛波醇酯在Ras的激活作用下迅速聚集，导致ERK1/2和P90RSK的活化。胰岛素以及IGF-1可以在几小时内激活PI-3-激酶及其效应酶PKB，而EGF的作用较弱。因此，这种激活效应是胰岛素/IGF -1的一个特有特征，可能会促进有丝分裂的产生。TSH和cAMP作为有丝分裂原而言，是非常独特的，因为犬甲状腺细胞中，TSH和cAMP不能激活Ras、PI-3K-PKB信号通路，以及MAP激酶[3]。人甲状腺细胞中，TSH 和 cAMP同样也不能激活的MAP激酶。mTOR通路（最初由P70S6K磷酸化激活）是生长因子以及cAMP依赖的有丝分裂级联的唯一早期汇合中心。通过多种肿瘤抑制剂的磷酸化失活作用，生长因子以及IGF-1可以激活mTOR-复合体（mTORC1），而通过PRAS40的磷酸化作用，PKB和PKA（分别由IGF-1/胰岛素和TSH激活）可以激活mTORC1。
3.细胞周期调控蛋白：细胞增殖失去正常的控制是增殖性疾病的重要特征，甲状腺肿和Graves病都存在甲状腺细胞的过度增生。在研究增殖性疾病异常的细胞分化和生长时，发现了与细胞周期调控有关的蛋白。细胞周期是指连续分裂的细胞从前一次有丝分裂结束到下一次有丝分裂结束所经历的整个过程，分为4个时期：G1、S、G2、M。其中G1、S、G2 期为分裂间期，M期为有丝分裂期。在G1期，如果失去促进增殖的刺激，细胞将停止于G1期不再向S期过渡，进而停止增殖，称为G0期。在细胞周期的运行中，有两个主要的调控点，也称为检测点，一个处于G1/S转折点，是控制细胞进入S期的检测点；另一个是处于G2/M转折点，是控制细胞进入M期的检测点。在一般情况下，细胞内外的各种信号通过检测点使细胞增殖发生停滞，不能继续分裂下去；如果检测点功能异常，细胞分裂不能有效控制，则导致细胞无限增殖。而对细胞周期调控而言，G1/S检测点最为重要。
细胞周期的不同时点由不同的细胞周期蛋白调控。细胞周期蛋白是一类随着细胞时相变化而发生相应变化的蛋白质，在细胞周期调控中起到关键作用。细胞周期蛋白作为细胞周期调节因子之一，对细胞周期进行正性调节，若其在人类多种疾病中过度表达，与肿瘤和组织增殖的发生发展密切相关。细胞周期蛋白在功能上主要与特定的细胞周期蛋白依赖性激酶（CKD）形成复合物，进而通过对特异底物的磷酸化以周期依赖的方式促进细胞增生。细胞周期蛋白含量随细胞周期而变化，在其相应周期时达到含量和活性的高峰，激活相应的CDK后迅速降解。不同细胞的周期长短主要取决于G1期时间长短，故G1-S期调控点最为重要。Cyclin D1是G1期到S期转换过程中最为重要的调控因子，由Cyclin D1与CDK结合并通过调节其活性而发挥作用。Cyclin D1是细胞DNA合成以及通过G1/S期检测点的正向调控因子。细胞周期蛋白B1（Cyclin B1）是典型的G2/M期周期蛋白，G2/M期转换的关键调控因子是Cyclin B1/p34cdc2复合物，Cyclin B1在S期开始合成，并在G2期定位于细胞质，与p34cdc2结合形成有丝分裂促进因子（MPF），促进细胞从G2期进入M期，从而完成有丝分裂[36]。
Cyclin D1作为一种癌基因，在许多增殖性疾病中过度表达。在生长因子的诱导下，Cyclin D1 在G1初期达到高峰，于G1中晚期降解。由Cyclin D1和依赖细胞周期素激酶4/6（CDK4/6）装配而成为全酶，促进视网膜细胞瘤蛋白（pRb）磷酸化，消除其抑制生长功能，从而启动细胞周期，使细胞从G0期进入G1期，并推动G1期前进，从而参与细胞增殖。当Cyclin D1表达失控时，则引起细胞增殖周期失调，从而导致细胞过度增生。Cyclin D1的过度表达使细胞周期G1期缩短，细胞生长对有丝分裂原和黏附信号的需求降低，导致细胞过度增生，组织体积增大。
IGF-1同时具有促进有丝分裂作用，可刺激RNA、DNA的合成和细胞增殖，参与细胞增殖周期的调控，使处于静止期的细胞进入和完成细胞周期。IGF-1可以调节细胞周期过程中涉及的多种分子的表达和活性。在肿瘤细胞的研究中发现IGF-1能上调Cyclin D1的表达，提示IGF-1与Cyclin D1在细胞增殖中存在重要的联系和作用[37]。IGF-1同样可以上调甲状腺细胞Cyclin D1的水平，促进细胞周期的进展，降低G0/G1细胞数目，增加S期细胞数目，这证明IGF-1同样可以促进甲状腺细胞周期的进展[38]。
4.增殖和分化：腺垂体分泌的TSH和甲状腺自分泌以及旁分泌的生长因子在调控甲状腺生长和功能过程中起到重要作用。IGF-1作为甲状腺自分泌以及旁分泌的生长因子，调节甲状腺上皮细胞的生长，IGF-1在甲状腺病理和生理性生长过程中起着非常重要的作用。IGF-1可以与TSH协同促进TPO和Tg mRNA的表达、碘的摄取和有机化。有报道提示IGF-1刺激Tg表达是通过调节甲状腺转录因子2（TTF2）水平实现的[39]。表皮生长因子（EGF）是体外甲状腺上皮细胞（TEC）的强效生长因子。EGF可以与IGF-1协同刺激甲状腺上皮细胞的生长。与IGF相比，EGF可逆地抑制人甲状腺上皮细胞的分化，抑制碘的摄取和活化，并且减少TSH诱导的cAMP的生成。成纤维细胞生长因子（FGF）是甲状腺自分泌、旁分泌的生长因子，不仅刺激甲状腺上皮细胞的生长，而且刺激间质细胞、脉管系统的外膜细胞、平滑肌细胞和内皮细胞的生长。FGF可以增加FRTL-5细胞对胸腺嘧啶的摄取，并且增强TSH的促有丝分裂作用。TGFβ是甲状腺的一个自分泌生长因子。在人原代培养的甲状腺上皮细胞以及FRTL-5细胞均证实TGFβ抑制其增殖。这种效应可能与抑制增殖性细胞核抗原（PCNA）的合成有关[39]。Holting等发现转化生长因子β（Transforming Growth Factor β，TGFβ）能抑制甲状腺滤泡状癌以及乳头状癌的生长、转移及浸润，促进肿瘤细胞和基质的黏附性，表明TGFβ是抑制甲状腺肿瘤发生发展的一种重要因子[40]。
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