干细胞相关因子OCT-4增强EMT在难治性甲状腺癌放射碘抵抗中的作用机制研究

Radioiodine therapy resistant is the bottleneck in treatment of refractory thyroid cancers, which have iodine metabolism defects and are not sensitive to radioiodine. Studies have proved that stem cell associated genes were relevant to radiotherapy resistant in many cancers. Our previous study found that the stem cell associated factor OCT-4 is relevant to the radioiodine resistance of thyroid cancers. There is emerging evidence to suggest that EMT can cause defects of iodine metabolism in thyroid cancers. Further in vitro studies found that over expression of OCT-4 can enhance the epithelial-mesenchymal transition (EMT) process in thyroid cancers and wnt/β-catenin pathway may be involved. Based on the above findings, we speculate that OCT-4 may lead to radioiodine resistance in thyroid cancers by enhancing EMT via Wnt / β-catenin pathway. Our group plans to carry out a series of in vivo and in vitro experiments, to investigate the roles of OCT-4 on radioiodine resistance in thyroid cancers and the potential mechanism.

放射碘治疗抵抗是难治性甲状腺癌的治疗瓶颈，其涉及到甲状腺癌（TC）细胞碘代谢和放疗固有敏感性两个环节。已有研究证明干细胞相关基因与多种肿瘤的放疗抵抗有关；课题组前期研究发现干细胞相关因子OCT-4的表达随着TC细胞放射碘抵抗程度的增加而明显升高，提示OCT-4可能与TC放射碘抵抗相关；新近研究表明上皮-间质转化（EMT）在难治性甲状腺癌放射碘抵抗中发挥着重要作用，其与TC碘代谢异常有关；我们进一步的细胞功能研究发现，过表达OCT-4可增强TC的EMT作用，且wnt/β-catenin 通路可能参与其中。因此，我们提出科学假说：OCT-4通过调控wnt/β-catenin 通路增强EMT从而导致TC放射碘治疗抵抗。鉴此，本项目拟通过体内、外实验研究干细胞相关基因OCT-4对难治性TC放射碘抵抗的作用机制，本研究为难治性TC逆转放射碘抵抗的分子靶向治疗提供新的科学依据，裨益临床治疗。

放射碘治疗抵抗是难治性甲状腺癌的治疗瓶颈，其涉及到甲状腺癌细胞碘代谢和放疗固有敏感性两个环节。本项目通过基因芯片检查发现干细胞相关基因OCT-4在难治性甲状腺癌中高表达，利用免疫组化检测发现OCT-4与甲状腺癌碘抵抗密切相关；进而通过构建OCT-4过表达IHH4甲状腺乳头状癌细胞株及OCT-4敲除8505-C甲状腺未分化癌细胞株，开展CCK-8增殖实验、transwell侵袭和迁移实验证实OCT-4对甲状腺癌细胞增殖、侵袭转移能力存在重要影响。并利用Na131I干预实验，证实OCT-4基因通过Wnt/β-catenin信号通路调控NIS基因表达，进而参与了甲状腺癌细胞碘转运过程。最后，通过动物实验证实OCT4过表达可在体内显著增加IHH4细胞的成瘤能力，并且降低甲状腺乳头状癌IHH4细胞对131I放射治疗的敏感性。综上所述，本项目为探讨干细胞相关基因OCT-4引起难治性TC放射碘抵抗的相关机制奠定了一定基础，并为难治性TC逆转放射碘抵抗的分子靶向治疗提供新的方向和思路。项目资助发表相关论文7篇，1篇已投稿，培养硕士生2名。