MGAT3通过催化平分型GlcNAc糖基化修饰LAMA3调控甲状腺微小乳头状癌颈侧淋巴结转移的作用及机制研究

甲状腺微小乳头状癌（PTMC）在全球范围内呈爆发式增长，多数具有惰性特点，然而部分患者早期即可出现颈侧淋巴结转移。目前尚无可靠方法预测PTMC颈侧淋巴结转移风险，相关分子机制不明。前期研究发现伴颈侧淋巴结转移的PTMC患者MGAT3及其催化的平分型N-糖链表达显著增高，反映了更高的肿瘤侵袭潜能，而MGAT3表达下调能抑制TPC-1细胞的侵袭迁移能力，但内在分子机制不明。N糖基化质谱分析显示LAMA3可能作为平分型GlcNAc修饰的关键靶蛋白，其在甲状腺癌中低表达，具有抑制肿瘤侵袭转移的作用。申请者遂提出假设：MGAT3可能通过催化平分型GlcNAc糖基化修饰LAMA3，抑制其与integrin的结合，降低细胞粘附功能并激活下游信号通路，促进PTMC侵袭转移。本项目拟从临床-细胞-类器官-动物四个层面探索MGAT3调控PTMC颈侧淋巴结转移的分子机制，为PTMC的精细化风险分层提供理论依据。

Papillary thyroid microcarcinoma (PTMC) has exploded on a global scale, and most of them are indolent. However, the first symptoms of some patients can be manifested as lateral cervical lymph node metastasis. At present, there is no reliable method to predict the risk of PTMC lateral cervical lymph node metastasis, and the molecular mechanism involved is still unclear.The applicant’s previous study found that PTMC patients with lateral cervical lymph node metastasis had significantly higher expression of MGAT3 and bisected N-glycans, reflecting higher tumor invasion potential, while low expression of MGAT3 inhibited invasion and migration ability of TPC-1 cells. Whereas, the molecular mechanism was not clear. N-glycosylation protein mass spectrometry analysis showed that LAMA3 may be a key target glycoprotein with bisecting GlcNAc modification. LAMA3 was down-expressed in thyroid cancer and had the effect of inhibiting tumor invasion and metastasis. The applicant proposes the following scientific hypothesis: the bisecting GlcNAc on LAMA3 catalyzed by MGAT3, may inhibit the binding of LAMA3 and integrin clusters, reduce cell adhesion function and activate the downstream signaling pathways, and furtherly promote the invasion and metastasis ability of PTMC. This project intends to explore the molecular mechanism of MGAT3 regulating lateral cervical lymph node metastasis of PTMC from the four levels of clinic-cell-organoid-animal, and provide a theoretical basis for the refined risk stratification of PTMC.