雌激素受体及RET/PTC、miR-34b在甲状腺乳头状癌生长、转移中的作用及靶向调控

Lymph node metastasis seriously affects the prognosis of papillary thyroid carcinoma (PTC). Recently, the relationship between estrogen receptor (ER) and PTC progression has received great attention. Our preliminary study found that 53% of patients with PTC expressed ER in the tumor tissue. Compared to ER-negative patients, the rate of lymph node metastasis in ER-positive patients was significantly higher. To analyze the effect of ER on PTC, estrogen (E2) was used to stimulate ER-positive PTC cell lines. The results showed that, after E2 stimulation, the expression of fusion gene RET/PTC in PTC cells was increased, while that of tumor suppressor molecule miR-34b was decreased. The functions of fusion gene and microRNA during tumor occurrence and development have been recognized, but the mechanisms are unclear. Therefore, we assume that the high expression of ER in the PTC tissues might promote tumor growth and metastasis through the promotion of the RET/PTC and inhibition of miR-34b. This project aims to determine: ①whether ER regulates tumor cell epithelial-mesenchymal transition, proliferation, apoptosis, migration or autophagy through the RET/ PTC/mTOR pathway, ②whether ER regulates cell cycle-related proteins through the down-regulation of miR-34b, and further promote the growth of the PTC？This project will provide a novel theoretical basis for the treatment of ER-positive patients with PTC using estrogen receptor antagonist.

甲状腺乳头状癌（PTC）的淋巴结转移严重影响其预后。近年雌激素受体（ER）与PTC发生发展的相关性受到重视。我们的研究发现53%的PTC组织ER阳性，ER阳性的患者淋巴结转移率明显高于ER阴性的患者。予雌激素(E2)刺激ER阳性的PTC细胞株，发现PTC细胞RET/PTC融合基因表达上调，而抑癌分子miR-34b表达下调。基于融合基因和MicroRNA在肿瘤发生发展中的重要作用，我们假设PTC组织中高表达的ER可能通过促进RET/PTC，抑制miR-34b的表达促进了肿瘤的生长及转移。在此基础上，拟结合干预手段探讨：ER是否①通过RET/PTC/mTOR通路调控了PTC肿瘤细胞的上皮间叶转变、增殖、凋亡、迁移、侵袭和自噬；②通过miR-34b调控细胞周期相关蛋白的表达，进一步促进PTC的生长。从而阐明ER在PTC发生发展中的作用，为ER拮抗剂干预PTC提供新思路及新策略。

甲状腺乳头状癌（PTC）的淋巴结转移严重影响其预后。① 近年来雌激素受体（ER）与肿瘤的关系逐渐为国内外学者所重视。我们的研究发现ERａ阳性的PTC患者淋巴结转移率明显高于ER阴性的患者。miR-219–5p在PTC组织中的表达是下调的。miR-219–5p与性别、肿瘤大小和淋巴结转移显著相关。miR-219–5p的低表达与ERａ的高表达具有相关性。在PTC细胞株的研究中发现，PTC细胞miR-219–5p表达的增加抑制了PTC细胞的增殖与迁移，促进了凋亡。进一步研究发现PTC的发生发展过程中，ERａ是miR-219–5p的靶基因。更重要的是，PTC细胞上ERａ的过表达减弱了miR-219–5p的对肿瘤的抑制作用。此外，雌激素通过RET/PTC通路调控了PTC肿瘤细胞的生物学行为。② 炎症在肿瘤发展和转移中发挥重要作用。我们也发现人PTC组织中与炎症相关的低分子量透明质酸（LMW-HA）刺激TLR4通过CXCR7促进了PTC的转移。这些研究为阐明炎症状态下LMW-HA /TLR4在PTC发生发展和转移中的作用机制，建立特异性雌激素受体为靶向防治新策略提供了理论基础和实验依据。