ERBB2突变激活PABPC3增强糖酵解在胆囊癌发生发展中的作用及机制研究

胆囊癌是胆道系统常见的恶性肿瘤，手术根治率低，放化疗效果不佳，预后差。我们前期通过全外显子组测序发现ERBB2/3突变是胆囊癌的显著特征。结合TCGA数据库证实ERBB2/3突变存在互斥，ERBB2 S310F是最高频突变，位于胞外配体结合结构域，PET-CT显示ERBB2 S310F突变的肿瘤代谢负荷明显高于未突变及其他突变的胆囊癌；转录组测序明确ERBB2 S310F突变的胆囊癌糖酵解相关基因显著上调且胆囊癌糖酵解代谢增强；磷酸化质谱分析显示ERBB2 S310F突变促进PABPC3 S315位点磷酸化，增强了糖酵解相关基因mRNA的稳定和翻译。据此，本课题将深入探索ERBB2 S310F突变促进PABPC3磷酸化，PABPC3 S315磷酸化对mRNA稳定性和翻译效率的调控，阐明ERBB2 S310F突变调控糖酵解代谢，促进胆囊癌发生发展的作用机制，为胆囊癌治疗探寻潜在靶点。

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract, the prognosis remains poor due to the low rate of radical Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract, the prognosis remains poor due to the low rate of radical operation and the poor effect of chemoradiotherapy. We previously found that ERBB2/3 mutations were the significant character of GBC through whole-exome sequencing. ERBB2/3 mutations were mutually exclusive in the TCGA database and our study. ERBB2 S310F mutation was the most frequent mutation locating in the extracellular ligand-binding domain of ERBB2. PET-CT results showed gallbladder cancer with ERBB2 S310F mutation suffered heavy metabolic burden compared with non-mutated or other ERBB2 mutant gallbladder cancer. RNA-seq results confirmed that the related genes of glycolysis were significantly enriched and up-regulated in ERBB2 S310F mutant gallbladder cancer, which promoted gallbladder cancer glycolysis, ERBB2 S310F mutation promoted the phosphorylation of PABPC3 S315 through mass spectrometry analysis, which promoted the mRNA stability and translation efficiency of the related genes of glycolysis. Therefore, the aim of this study is to clarify the function and molecular mechanism of ERBB2 S310F mutation promoting glycolysis in the development of gallbladder cancer and provide potential targets for therapy.