Hippo-YAP轴在分化型甲状腺癌糖/碘代谢重构中的作用及机制

18F-FDG/131I "flip-flop" phenomenon reflects the differentiation degree and prognosis of differentiated thyroid carcinoma (DTC) and reprogramming of glucose/iodine metabolism might be a promising treatment option for this disease. However, the underlying mechanism of this phenomenon has not been clearly elucidated. Based on our previous work and literature reports, we hypothesize that Hippo-YAP axis activation can directly reduce the expression of GLUT1 in DTC and meanwhile inhibit the MAPK pathway which finally increasing the expression of NIS indirectly. Thus, this project will take papillary thyroid carcinoma (PTC) as the research subject which accounts for the vast majority of DTC. By using YAP gene over expression/knock down PTC cell lines and YAP-TEADs specific inhibitor, we are trying to validate and elucidate the effect and mechanism of Hippo-YAP signal axis on the reprogramming of glucose/iodine metabolism in PTC at histology, cytology and animal model levels, respectively. This project will help to unveil the potential mechanism underlying the 18F-FDG/131I "flip-flop" phenomenon of DTC and the results could provide new targets and methods for the treatment of DTC, especially for radioiodine refractory disease.

18F-FDG/131I摄取反转可反应分化型甲状腺癌（DTC）的分化程度及预后，重构DTC糖/碘代谢或可成为其治疗的有力途径，但该现象背后的相关机制尚未清晰阐明。本项目结合预实验结果、前期研究及文献报道，提出科学假设：Hippo-YAP轴激活可直接降低DTC细胞GLUT1的表达；同时通过抑制MAPK通路信号流，间接增加NIS的表达。为此，本研究以占DTC绝大多数的乳头状甲状腺癌（PTC）为研究对象，采用YAP基因过表达及沉默的PTC细胞株为研究工具，同时平行应用YAP-TEADs特异性抑制剂，在组织学、细胞学及动物模型水平分别验证并阐明Hippo-YAP信号轴对PTC糖/碘代谢重构的作用及机制。本项目的开展有助于阐明DTC糖/碘摄取反转现象背后的潜在机制，研究结果可为DTC的治疗特别是碘-131难治性DTC的临床诊治提供新的靶点及方法。

侵袭性/进展性转移性甲状腺乳头状癌(PTC)的治疗非常困难。分化型甲状腺癌在去分化过程中会出现放射性碘（碘-131）和F-18氟脱氧葡萄糖(18F-FDG)摄取的反转现象。然而，这一现象背后的机制尚未阐明。缺氧是促进癌症进展和糖酵解的重要微环境因素。Hippo-YAP是一种高度保守的肿瘤抑制通路，有助于癌症代谢重编程。因此，我们研究了PTC中葡萄糖/碘代谢重编程的潜在分子机制，重点关注肿瘤缺氧微环境和Hippo-YAP信号通路。本研究采用免疫组化染色法检测PTC癌和癌旁组织中HIF-1α、YAP、葡萄糖转运蛋白1 (GLUT1)、钠碘同乡转运体(NIS)的表达。PTC细胞分别在常氧(20% O2)和低氧(1% O2)条件下培养，检测糖酵解水平和NIS的表达。进一步研究了PTC细胞葡萄糖/碘代谢重编程的分子机制。最后，我们通过建立裸鼠皮下异种移植模型在体内验证了结果。研究发现PTC组织中HIF-1α、YAP和GLUT1的表达水平上调，YAP的表达与HIF-1α、GLUT1和TNM分期呈正相关。NIS的表达与YAP呈负相关。此外，体外研究表明，缺氧诱导的YAP激活对于加速糖酵解和降低PTC细胞中NIS的表达至关重要。抑制YAP后上述现象可以被逆转。缺氧抑制Hippo信号通路，导致YAP磷酸化失活，进一步促进YAP在PTC细胞中的核定位，其机制是低氧应激促进YAP与核内HIF-1α结合，从而维持了HIF-1α蛋白的稳定性。YAP/HIF-1α复合物直接激活GLUT1转录，加速糖酵解。同时HIF-1α/YAP信号通路可能通过激活MAPK信号通路的间接作用降低NIS的表达。体内研究进一步证实，HIF-1α/YAP信号通路介导了葡萄糖/碘代谢重编程从而促进了PTC的恶性进程。总之，本研究揭示了HIF-1α/YAP信号通路在PTC葡萄糖/碘代谢重构中的作用及潜在机制。本研究结果提示抑制HIF-1α/YAP信号通路对难治性PTC具有潜在的治疗前景。