TTF-1的表达与甲状腺乳头状癌的上皮间质转化及临床预后的相关性研究

Papillary thyroid carcinoma (PTC) is the most common endocrine tumor, with the invasiveness and metastasis closely involved in the epithelial-mesenchymal transition (EMT) in our previous study. Recently, it was reported that TTF-1 could inhibit TGF-β mediated EMT in lung adenocarcinoma cells. TTF-1, a major switch in regulating the transcription of thyroid functional proteins, is more specificially expressed in thyroid neoplasms, however, its role in the EMT process, invasiveness, and metastasis of PTC is by far unknown. Our preliminary study revealed that the presence of the loss of cellular polarity/adhesiveness in the invasive front, served as the morphological characteristics of EMT, was positively correlated with extrathyroid invasion, lymph node metastasis, and unfavorable disease-free survival in PTC cases, and the expression of TTF-1 was significantly decreased in the carcinoma cells with loss of cellular polarity/adhesiveness. Therefore, we suppose that TTF-1 may enhance the invasiveness and metastasis of PTC through EMT process. In the present study, the correlation between the expression difference of TTF-1 in the invasive front and tumor center and the invasiveness as well as metastasis of PTC tissue will be analyzed, and its survival impact will be detected. TTF-1 high expression/ loss of express cell lines will be constructed to analyze the effect of TTF-1 in the growth and EMT process of thyroid carcinoma cells. Inhibitors of different signal transduction pathways will be used to inhibit the corresponding pathways in order to expore the functional mechamism of TTF-1 in the EMT process, so as to provide a novel strategy for the molecular targeted therapy of PTC.

甲状腺乳头状癌（PTC）是最常见内分泌肿瘤，我们的既往研究表明其浸润与转移与上皮间质转化（EMT）密切相关。近年，TTF-1被报道抑制TGF-β介导的肺腺癌细胞的EMT过程。TTF-1在甲状腺肿瘤中的表达更具特异性，但其对PTC的EMT、浸润及转移的影响仍然不清。我们前期研究发现，PTC中作为EMT组织学特征的浸润前沿癌细胞极性丧失/粘附性下降与腺外浸润、淋巴结转移及无病生存率均密切相关，而极性丧失/粘附性下降的癌细胞其TTF-1表达明显减少，据此推测TTF-1表达减少可能通过EMT增加PTC的浸润及转移。本研究拟解析PTC临床标本中TTF-1在浸润前沿及癌中心的表达差异与癌浸润、转移及临床预后的关系；构建TTF-1高表达、失表达细胞株，探索TTF-1对癌细胞生长及EMT的影响；利用信号转导通路抑制剂抑制不同的信号途径探讨TTF-1影响EMT的作用机制，从而为PTC的分子靶向治疗提供新的策

甲状腺乳头状癌（PTC）是最常见的内分泌肿瘤，我们的既往研究表明其浸润与转移与上皮间质转化（EMT）密切相关。近年，TTF-1被报到抑制TGF-β介导的肺腺癌细胞的EMT过程。TTF-1在甲状腺肿瘤中的表达更具特异性，但其对PTC的EMT、浸润及转移的影响仍然不清。我们的前驱研究发现，PTC中作为EMT组织学特征的浸润前沿癌细胞极性丧失/粘附性下降与甲状腺外浸润、淋巴结转移及无病生存率均密切相关。我们对北京大学肿瘤医院（北京市肿瘤防治研究所）2012-2013年的原发甲状腺乳头状癌126例进行了TTF-1，BRAF V600E，PD-L1，PD-1，EMA，TG，E-cadherin，β-catenin，Ki-67及vimentin等与细胞的粘附性、极性、EMT或与甲状腺癌细胞的分化程度、免疫治疗相关的标记物进行了免疫组化染色，发现BRAF V600E、EMA及PD-L1的表达均与浸润前沿癌细胞极性丧失/粘附性下降的出现有统计学相关性。TTF-1的表达与浸润前沿癌细胞极性丧失/粘附性下降的出现有一定的相关性，但不具有统计学意义。对甲状腺乳头状癌组织的浸润前沿及癌中心分别取材，提取总mRNA, RT-PCR及QRT-PCR法检测到浸润前沿癌细胞TTF-1的表达明显低于癌中心。构建了TTF-1高表达及失表达甲状腺癌细胞系，发现失表达细胞系细胞增殖速度加快，粘附性下降，且浸润及迁移能力增快。通过对细胞传导通路的研究发现，TTF-1通过MAPK通路调节细胞的增值速度、EMT表型改变及迁移能力。. 本研究揭示了TTF-1在PTC的浸润前沿与癌中心的表达差异与EMT的关系，阐明了TTF-1的表达对甲状腺癌细胞的生长及EMT表型的影响，并揭示了TTF-1在甲状腺乳头状癌EMT过程中可能的作用机制，为甲状腺癌的良好预后提供了诠释，并为甲状腺癌治疗靶点的选择提供了新的数据支持。

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