甲状腺癌是内分泌系统最常见的恶性肿瘤，其发病率急剧增加，严重影响国民健康。STAG2是黏连蛋白复合体中重要的亚基，参与有丝分裂后期染色体的分离及姐妹染色单体的形成。最近，有研究发现在BRAFV600E突变的黑色素瘤中STAG2的失活突变可导致黑色素瘤耐药。通过分析TCGA数据库，我们发现相较于癌旁组织，STAG2基因在甲状腺癌组织中的表达显著下调。进一步的细胞实验证实下调STAG2并不影响BRAFV600E突变的甲状腺癌细胞的增殖，以及对MEK激酶抑制剂的敏感性，却显著影响肿瘤细胞对谷氨酰胺的依赖性。根据我们的前期结果，我们推测STAG2可能通过调控ERK/AKT/GSK3β/c-Myc反馈通路影响甲状腺癌细胞的谷氨酰胺代谢。在此基础上，本项目拟通过一系列体内外实验验证上述假设，并初步明确谷氨酰胺代谢酶抑制剂对甲状腺癌的治疗作用，为甲状腺癌的治疗提供新的思路和策略。

Thyroid cancer is the most common malignant tumor of the endocrine system. In recent years, the incidence of thyroid cancer has dramatically increased in the world. In addition to classical treatments like surgery and radioactive iodine, molecular targeted therapy has begun to enter the clinic and achieved benefits in thyroid cancer. However, thyroid cancer with BRAFV600E mutation has a higher risk of drug resistance, mainly due to the feedback mechanism in this type of thyroid cancer. STAG2 is an important subunit in cohinsin complex, which is involved in the segregation of chromosomes during the late mitosis and the formation of sister chromatids. Inactivation mutations of STAG2 in BRAFV600E mutant melanoma is one of the causes of melanoma drug resistance. Through analyzing the TCGA database, we found that STAG2 was frequently down-regulated in thyroid cancers. Further functional studies showed that down-regulation of STAG2 did not affect thyroid cancer cell proliferation, and the sensitivity of BRAFV600E mutant thyroid cancer cells to MEK inhibitors, but significantly affected glutamine dependence of thyroid cancer cells. Based on our preliminary data, we speculate that STAG2 may affect glutamine metabolism of thyroid cancer cells through modulating the ERK/AKT/GSK3β/c-Myc feedback pathway. Thus, the aims of this project were to validate the above hypothesis through a series of in vitro and in vivo experiments, and investigate the feasibility for the treatment of thyroid cancer through targeting glutamine metabolic enzymes, thereby providing a new strategy for thyroid cancer therapy.