膜结合蛋白VCP协同其锚定蛋白UBXD1调控甲状腺乳头状癌侵袭转移的机制研究

There are several aggressive forms of thyroid papillary carcinoma (PTC) prone to metastasis, which will affect the prognosis of PTC. Up to now, the related mechanisms remain unclear, and the stratification diagnosis for PTC patients is hampered by the shortage of highly efficient biomarkers. The VCP, a membrane bound protein, is acting as an essential molecular chaperone of AAA ATP enzymes, and plays an important role in the development and progression of various malignant tumors. The complex with different anchors is the molecular basis of its precise regulation. Our previous studies showed that VCP was generally overexpressed in PTC tissues, and the expression of UBXD1 was closely related to metastasis and prognosis. Down-regulation of UBXD1 promoted the invasion and migration of PTC cells in vitro. These results suggests that UBXD1 plays an important role in the progress of PTC, and it is a potential biomarker for the prediction of high risk PTC patients. Based on this, we will further clarify the mechanism of VCP and UBXD1 in regulating the invasion and metastasis of PTC in clinical samples, cell models and nude mice orthotopic transplanted tumor model, to clarify the correlation between its expression and invasion and prognosis of patients. This study attempts to reveal the new regulatory mechanism of PTC's malignant evolution in order to provide theoretical basis and experimental basis for PTC stratified diagnosis and treatment.

部分甲状腺乳头状癌（PTC）恶性程度高，易发生转移，影响预后。然而此类PTC发生机制不明，缺乏有效分子标志物，是临床分层诊疗的主要障碍。膜结合蛋白VCP，作为AAAATP酶的分子伴侣，在多种恶性肿瘤发生发展中发挥着重要作用，与不同锚定蛋白形成复合物是构成其精准调控的分子基础。我们前期研究结果显示PTC组织中VCP普遍强阳性表达，而其上游锚定蛋白UBXD1则主要阳性表达于PTC未转移组，且与预后相关；体外实验示下调UBXD1表达可促进PTC细胞侵袭迁移，提示UBXD1表达下调很可能是预警PTC高风险的关键分子事件。基于此,本研究将在临床样本、细胞模型及裸鼠原位移植瘤模型层面论证VCP协同UBXD1调控PTC侵袭转移的机制，明确其表达与PTC侵袭转移及预后的相关性，以期揭示PTC恶性演进的新调控机制，为分层诊疗提供理论基础与实验依据。

甲状腺乳头状癌（PTC）总体预后良好，但部分恶性程度高，易发生转移，影响预后。然而此类PTC发生机制不明，缺乏有效分子标志物，是临床分层诊疗的主要障碍。本课题通过蛋白质表达谱分析发现UBXD1在PTC转移与非转移组间表达存在显著差异；通过临床样本进一步确证UBXD1与PTC侵袭转移及预后密切相关；体外细胞功能实验示UBXD1表达可影响PTC细胞迁移、侵袭，但不影响增殖；裸鼠甲状腺癌肺转移模型示UBXD1表达可影响PTC细胞转移能力；通过Westernblot方法分析UBXD1表达对自噬、凋亡相关蛋白表达水平的影响，发现UBXD1可能通过p-JNK/Bax/caspase3信号促进细胞凋亡，发挥抑癌作用。综合上述结果，本研究阐明了UBXD1参与调控PTC侵袭转移的分子机制，为PTC患者分层诊疗奠定理论基础与实验依据。项目资助发表SCI论文5篇，待发表1篇。参加国内外学术交流4次。培养硕士生1名，且已经取得硕士学位。项目投入经费20万元，支出18.7964万元，各项支出基本与预算相符。剩余经费1.2036万元，剩余经费计划用于本项目研究后续支出。