PLA2G16/GPD2-Wnt/β-catenin正反馈环路对胆囊癌增殖、转移及铁死亡的功能和机制研究

胆囊癌是胆道系统常见恶性肿瘤，预后极差。因此，深入研究胆囊癌发生发展的分子生物学机制，对实现胆囊癌的早期诊断和精准治疗具有重要意义。申请者在前期工作中利用胆囊癌原发灶及癌旁正常组织进行全转录组测序，筛选出了在胆囊癌中高表达并与不良预后有关的脂肪特异性磷脂酶基因PLA2G16。通过生物信息学分析和一系列体外及体内实验证实了PLA2G16具有促进胆囊癌细胞增殖、转移及抑制铁死亡的重要作用，并发现了胆囊癌细胞中存在PLA2G16/GPD2-Wnt/β-catenin正反馈环路，导致促癌信号恶性循环。在此基础上，本课题将进一步明确PLA2G16在胆囊癌的表达情况、生物学行为特征及其与胆囊癌病理分期及患者预后的关系。深入研究此正反馈环路的分子互作模式及其对胆囊癌增殖、转移和铁死亡的作用，并探索针对其关键分子对胆囊癌的治疗效果，进一步探索其作为胆囊癌诊治新靶点的临床意义。

Gallbladder cancer (GBC) is a common malignancy of the biliary tract with extremely poor prognosis. Therefore, it is of great importance to explore the mechanism of GBC for early diagnosis and precision treatment. In our preliminary work, PLA2G16 was screened out by whole transcriptome resequencing between GBC and adjacent tissues, which is highly expressed in GBC and associated with poor prognosis in GBC patients. A series of in vitro and in vivo experiments were conducted and showed that PLA2G16 could promote proliferation and metastasis while inhibiting ferroptosis in GBC cell. Moreover, we identified a PLA2G16/GPD2-Wnt/β-catenin positive feedback loop which lead to a vicious circle of pro-tumorigenic signals in GBC. On this basis, we will also explore the expression pattern and biological behavior of PLA2G16 in GBC, and its relationship with the pathological staging of GBC and patient prognosis. We will explore in depth the molecular interaction and biological functions of this positive feedback loop on the proliferation, metastasis and ferroptosis in GBC, and investigate the potential therapeutic effect of its key molecules on GBC, in order to clarify its clinical significance as novel biomarker for the diagnosis and treatment of GBC.