FAT1基因缺失通过JAK/STAT3通路调控PD-L1表达促进甲状腺髓样癌恶性进展的作用和其机制研究

甲状腺髓样癌（MTC）的发生发展机制尚未完全明确。前期测序发现，MTC存在高频FAT1基因缺失（Thyroid，2020），且队列中CD274基因（编码PD-L1）转录水平显著升高的肿瘤均存在FAT1基因缺失。申请人前期实验发现：（1）FAT1敲低促进MTC细胞增殖和迁移；（2）FAT1敲低导致JAK2/STAT3通路激活并通过增强CD274基因转录，导致PD-L1表达升高；（3）PD-L1表达与MTC复发相关（Thyroid，2019）；（4）MTC细胞中，FAT1蛋白与JAK/STAT通路负调节蛋白SHP2存在互作，同时SHP2与JAK2也存在互作。后续我们将结合临床样本分析、体内和体外实验进一步阐明FAT1-JAK2/STAT3-PD-L1轴的调控机制及其影响MTC恶性进展的分子机制。本研究将从新的角度阐明MTC的疾病进展机制，并为治疗靶点的开发提供理论依据。

The mechanism regarding initiation and development of medullary thyroid carcinoma (MTC) is not fully clarified. Our previous sequencing data revealed frequent FAT1 gene deletion in MTC (Thyroid, 2020), which was found in all tumors with significantly increased CD274 gene (encoding PD-L1) transcription in our cohort. Our previous experiments have shown (1) FAT1 knockdown promotes MTC cell proliferation and migration; (2) FAT1 knockdown leads to JAK2/STAT3 pathway activation and enhances PD-L1 expression via upregulating CD274 gene transcription; (3) PD-L1 expression is associated with MTC recurrence (Thyroid, 2019); (4) In MTC cells, FAT1 protein interacts with a negative regulator of JAK/STAT pathway called SHP2, while SHP2 also interacts with JAK2. In the follow-up study, we aim to combine clinical sample analysis, in vivo and in vitro experiments to further explore the molecular mechanism regarding FAT1-JAK2/STAT3-PD-L1 axis and its role in MTC progression. This study will elucidate the mechanism of MTC progression from a new perspective and provide theoretical basis for the development of therapeutic targets.