PIM1在放射性碘抵抗甲状腺癌中的作用及联合靶向BRAF突变治疗策略的研究

放射碘性抵抗甲状腺乳头状癌(PTC)的病因及后续治疗是甲状腺癌研究的热点和难点。目前研究表明，BRAF突变导致的钠碘同向转运体(NIS)失活是PTC放射性碘抵抗的重要原因，但具体机制尚不明确。本课题组前期研究发现：1) PIM1的高表达预示PTC的恶性表型以及更差的预后，且PIM1蛋白水平与PTC放射性碘抵抗以及NIS失活显著相关；2) BRAF突变可介导 PIM1的磷酸化，且该磷酸化位点对于PIM1的蛋白稳定性有重要调节作用；3) PIM1抑制剂联合BRAF突变抑制剂对杀伤人PTC细胞有明显协同作用。故本课题拟研究BRAF突变通过激活PIM1磷酸化并提高PIM1的蛋白稳定性，从而导致PTC放射性碘抵抗的机制。并进一步构建体外和体内放射性碘抵抗PTC模型，探索联合靶向PIM1与BRAF突变的治疗策略，为PTC临床治疗提供新思路。

The etiology and follow-up treatment of radioiodine-refractory thyroid papillary carcinoma (PTC) is attracted a great deal of attention in the field of thyroid cancer research. Current studies have demonstrated that the inactivation of sodium-iodide symporter NIS caused by BRAF mutation contributed to the radioiodine-refractory PTC, however the specific mechanism is not elucidated. Our previous studies revealed that: 1) PIM1 level predicted the malignant phenotype and worse outcome of PTC, and the high expression of PIM1 was significantly associated with radioiodine-refractory of PTC and inactivation of NIS; 2) BRAF mutation could mediate the phosphorylation of PIM1, which plays an important role in regulating the protein stability of PIM1; 3) BRAF mutation inhibitors combined with PIM1 inhibitors have a significant synergistic effect on reducing human PTC cells’ viability. Therefore, the aim of this project is to study the mechanism of BRAF mutation-mediated radioiodine-refractory PTC by activating PIM1 phosphorylation and improving the protein stability of PIM1. Furthermore, in vitro and in vivo radioiodine-refractory models will be set up to explore the clinical significance of combined targeted PIM1 and BRAF mutation therapy in radioiodine-refractory PTC.