p38MAPK-Atf2-Kin17调控分化型甲状腺癌放射性碘耐受的机制研究

The radioactive iodine tolerance is currently difficulty for the 131I treatment of differentiated thyroid carcinoma (DTC), but its mechanism has not been fully clarified. It is known that the DNA damage repair capacity improvements can cause tumor cells resistance and radiation resistance and the P38MAPK-Atf2 is the stress pathway for DNA damage, where as the Kin17 is the stress repair protein for DNA damage. However, whether p38MAPK-Atf2-Kin17 can cause the radioactive iodine tolerance in DTC has not been reported. The preliminary studies had found the level of Kin17 was upregulated in DTC and it was associated with clinical pathological parameters of DTC. Further in vitro studies, we found that the upregulation of Kin17 was regulated by p38MAPK-Atf2. Based on these results, this study intends to use lentivirvus transfection and RNAi to further verify the expression of Kin17 in DTC and its nuclear localization in vivo and in vitro model; and to further validation of the mechanisms of p38MAPK-Atf2-Kin17 in the radioactive iodine tolerance. It is also expected that this study will lay the foundation for subsequent translational medical research in DTC radioactive iodine tolerance.

131I治疗分化型甲状腺癌（DTC）过程中出现放射性碘耐受是目前DTC治疗的难点，但其机制仍未完全阐明。DNA损伤修复能力的增强可使肿瘤细胞出现耐药及放疗抵抗，p38MAPK-Atf2是DNA损伤应激通路，Kin17为DNA损伤应激修复蛋白，然而p38MAPK-Atf2-Kin17是否能导致DTC放射性碘耐受尚未见报道。本项目前期发现Kin17在DTC中表达上调且与病理参数相关，并进一步在体外研究发现Kin17的上调由p38MAPK-Atf2调控的基础上，拟结合DTC体内外模型采用细胞转染和RNAi等分子细胞生物学方法，观察Kin17在DTC中表达改变及核定位；揭示p38MAPK-Atf2-Kin17在DTC放射性碘耐受中的作用；探讨其涉及的机制；以期为DTC碘耐受的后续转化医学研究奠定基础。

131I治疗分化型甲状腺癌（DTC）过程中出现放射性碘耐受是目前DTC治疗的难点，但其机制仍未完全阐明。DNA损伤修复能力的增强可使肿瘤细胞出现耐药及放疗抵抗，p38MAPK-Atf2是DNA损伤应激通路，Kin17为DNA损伤应激修复蛋白，然而p38MAPK-Atf2-Kin17是否能导致DTC放射性碘耐受尚未见报道。本项目研究通过（1）在细胞水平观察 Kin17 在 DTC 表达改变及核定位，初步探讨 Kin17 在 DTC 放射性碘耐受的作用；（2）采用细胞转染和 RNAi 等分子细胞生物学方法，结合DTC 体外细胞模型与实验动物模型研究 Kin17 在 DTC 放射性碘耐受的功能研究及其涉及的机制；（3）阐明 P38MAPK-Atf2-Kin17 与 DTC 放射性碘耐受的关系。研究结果表明：在 131I治疗 DTC 过程中，P38MAPK-Atf2-Kin17 通路激活，Kin17 的上调使得 DNA不合理重组及复制能力增强，导致细胞增殖能力上升，从而导致 DTC 放射性碘耐受乃至失分化。