干扰素-γ诱导RFXAP调控胰腺癌染色体不稳定性的作用及其机制

Chromosome instability (CIN) plays pivotal role in promoting pancreatic cancer (PDAC) gene mutation and tumor progression. Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. However, the regulatory mechanism of CIN in PDAC and intervention technology were still unknown. Here, we found that the silencing of Regulatory Factor X-associated protein (RFXAP) was associated with impaired repair of DNA damage in PDAC, and interferon-γ (IFN-γ) can induce the expression of RFXAP. In this study, we aim to build a CIN scoring system based on next generation sequencing (NGS) of pancreatic cancer driver mutations, clarify the regulatory mechanism of CIN through RFXAP, and put forward the system of CIN intervention by IFN-γ. Firstly, PDAC CIN scoring system will be constructed based on NGS and clinical pathology. Secondly, the effect of RFXAP and IFN-γ in CIN can be expounded by the primary culture of PDAC using tissue explant method and CIN scoring system. Meanwhile we will clarify the regulatory mechanism of CIN by RFXAP through three different signaling pathways: APC/C、TGF-β and DNA damage repair. This study have directive significance to pancreatic cancer gene mutation and chromosome structure variation. It will provide a new evaluation tool for CIN and have potential value for clinical application.

染色体不稳定性（CIN）是驱动胰腺癌持续基因突变和肿瘤进展的重要动力，最新研究根据CIN将胰腺癌分为稳定、局部重排、广泛重排和不稳定4个亚型，但目前胰腺癌CIN的调控机制和干预技术仍未阐明。我们发现胰腺癌中调节因子X相关蛋白（RFXAP）表达沉默与DNA损伤修复异常有关，而干扰素-γ可以诱导RFXAP表达。本课题研究目标是建立基于胰腺癌驱动基因分析的CIN评分系统，阐明RFXAP对CIN的调控机制，提出IFN-γ干预CIN的方法。我们拟通过基因测序结合临床病理分析建立胰腺癌CIN评分系统，通过胰腺癌原代肿瘤培养和CIN评分研究干扰素-γ和RFXAP对染色体不稳定性的影响，并分别从APC/C、TGF-β、DNA损伤反应三条信号通路研究RFXAP调控CIN的机制。本课题将为CIN研究提供新的评价工具，对胰腺癌基因突变和染色体结构变异的研究具有重要的指导意义，同时也具有潜在的临床应用价值。

染色体不稳定性（CIN）是驱动胰腺癌持续基因突变和肿瘤发展的重要因素，但目前胰腺癌CIN的调控机制和干预技术仍未阐明。我们发现胰腺癌中调节因子X相关蛋白（RFXAP）表达沉默与DNA损伤修复异常有关，而干扰素-γ可以诱导RFXAP表达。本课题研究目标是建立基于胰腺癌驱动基因分析的CIN评分系统，阐明RFXAP对CIN的调控机制，提出IFN-γ干预CIN的方法。我们通过全外显子测序结合临床病理分析，首先建立了基于HRD基因的CIN评分系统，该评分系统是胰腺癌的独立危险因素，可以较好的评估患者预后，且效果优于基于驱动基因的CIN评分系统。我们明确了RFXAP在胰腺癌中表达水平及其预后价值，同时阐明其通过KDM4A调控DNA损伤修复功能和染色体不稳定性的机制，及IFN-γ诱导RFXAP表达干预胰腺癌染色体不稳定性的作用及机制。本项目研究结果为CIN研究提供了新的评价工具，对胰腺癌基因突变和染色体结构变异的研究具有重要的指导意义，同时也具有潜在的临床应用价值。