“染色体扩增型”胰岛素瘤成瘤机制的探索研究

胰岛素瘤是最常见的胰腺功能性神经内分泌肿瘤，既往研究发现YY1基因T372R点突变可解释至多约30%胰岛素瘤患者发病机制，剩余胰岛素瘤患者发病机制未知。本团队前期多组学测序发现胰岛素瘤“染色体扩增”事件与YY1基因突变存在互斥性，YY1基因野生型胰岛素瘤发生染色体扩增的比例高，因而提出“染色体扩增型”胰岛素瘤分子亚型这一概念。本研究拟通过转录组测序、定量蛋白质谱检测等手段，揭示“染色体扩增型”胰岛素瘤成瘤的成瘤机制及依赖的信号通路，进一步通过胰岛素瘤大鼠细胞系（INS-1）及小鼠模型（Rip1-Tag2小鼠），验证信号通路的作用；通过临床标本，验证信号通路在“染色体扩增型”胰岛素瘤中异常活化。综上，揭示“染色体扩增型”胰岛素成瘤机制，为设计靶向治疗药物提供关键性理论突破。

Insulinoma is one of the most common types of functional pancreatic neuroendocrine tumours. Previous studies revealed YY1 T372R point mutation could account for the pathogenesis for no more than 30% of insulinoma patients. However, the pathogenesis of the rest proportion of insulinomas remains unknown. Base on previous sequencing data, our team discovered that chromosome amplifications and YY1 mutations were mutually exclusive. In other word, insulinoma patient without YY1 mutation has a high probability of containing chromosome amplifications, thus the concept of 'chromosome amplification type' insulinoma was proposed. Current project aims to further elucidate the key pathogenic mechanism and key signaling pathways for 'chromosome amplification type' insulinoma by transcriptome sequencing and quantitative proteomics. Rat insulinoma cell line (Ins-1) and mouse insulinoma mouse model (Rip1-Tag2 mouse) will be used to validate the function of the key signaling pathways. Finally, human insulinoma sample will be used to test the activation status of the key signaling pathways. In summary, current project focuses on the discovery of pathogenic mechanism of 'chromosome amplification type' insulinoma, and provides pivotal information for future target therapy.