HMGB1通过自噬调控甲状腺癌细胞NIS表达及其摄碘率的机制研究

Radioiodine refractory differentiated thyroid cancer(RAIR-DTC) is a major obstacle to the successful treatment of thyroid carcinoma. Exploring the molecular mechanism of RAIR-DTC is still the topic in thyroid carcinoma research. Recently, our recent study demonstrated that exogenous sodium/iodide symporter（NIS）is a crucial regulator for treatment-resistant tumor therapy. Combined with data analysis and our former study, we found that NIS was expressed abundantly in RAIR-DTC compared with differentiated thyroid carcinoma (DTC), suggesting NIS played a potential contributory role in the pathogenesis in RAIR-DTC. Meanwhile, we also found that HMGB1 was expressed abundantly in DTC and HMGB1-medietaed autophagy induced NIS protein degradation in FTC133 cells. Based on these findings, our hypothesis is that HMGB1-mediated autophagy decreases NIS expression and radionuclide uptake contributing to the pathogenesis of RAIR-DTC. We will futherly determine whether HMGB1 regulated autophagy and NIS expression in FTC-133 cells and the signal pathways of HMGB1-mediated autophagy for RAIR-DTC . The fund supports the theory that HMGB1-mediated autophagy plays an important role in the tumorigenesis of RAIR-DTC and may be exploited as a new target for thyroid carcinoma treatment.

探讨碘难治性分化型甲状腺癌（RAIR-DTC）分子机制、提高患者存活率，仍然是甲状腺癌研究的热点。近期，项目组在《Clin Transl Oncol》上报道外源性NIS可能是难治性肿瘤重要的作用靶点。结合文献分析及项目组前期研究，发现RAIR-DTC组织较DTC组织NIS蛋白表达显著减少，提示NIS表达改变可能是RAIR-DTC产生的机制之一。同时，项目组发现HMGB1在DTC组织中高表达，且HMGB1介导的自噬途径可以降低FTC-133细胞NIS的表达。本课题在上述研究基础上，提出了HMGB1介导的自噬下调NIS表达及其摄碘率可能是RAIR-DT产生的假说。针对上述假说，本项目拟采用多种先进研究手段，进一步深入系统的探讨HMGB1通过自噬调控FTC-133细胞NIS表达及摄碘的分子机制。开展本项目可望揭示HMGB1调控甲状腺癌细胞自噬的分子机制，为寻找RAIR-DTC靶向治疗提供新思路。

研究发现，在自然状态下或治疗过程中逐渐失分化，丧失摄碘能力，最终发展为碘难治性分化型甲状腺癌，是甲状腺癌患者碘放射治疗失败的主要因素之一。溶酶体降解途径可能是甲状腺癌细胞介导了钠碘转运体（NIS）蛋白降解的重要途径之一。HMGB1在肿瘤发病及化疗耐药中扮演重要角色，研究发现HMGB1参与调控肿瘤细胞介导的自噬反应。本项目研究发现，HMGB1是FTC-133/TPC-1细胞中自噬介导NIS降解的关键调节因子。HMGB1在甲状腺癌组织中显著高表达，与甲状腺癌淋巴结转移及临床分期密切相关。RNA干扰基因敲除HMGB1表达能显著抑制HBSS诱导自噬所致NIS降解和细胞内碘摄取；抑制HMGB1表达能显著抑制LC3-II的转换和NIS蛋白的降解，其机制主要通过 AMPK/mTOR依赖的信号通路调节ROS的产生。此外，研究发现HMGB1是重要的促铁死亡因子，其机制与活性氧、铁过载及RAS/P38/JNK等相关；铁死亡诱导剂erastin能够促进HL-60/NRASQ61L细胞内活性氧（ROS）的发生及HMGB1从细胞核向细胞浆的移位，进而促进细胞铁死亡的发生，其机制可能与HMGB1调控细胞内铁过载可能与转铁蛋白受体1 (TfR1)过表达相关，RAS/P38/JNK信号通路参与了HMGB1对细胞内铁过载的调控。以上研究对碘难治性分化型甲状腺癌及耐药白血病的临床治疗，提供了新的理论思路，较为圆满的完成了结题。