SAGE1通过INTS3-hSSB1特异性调控肿瘤基因组稳定性的功能及分子机制研究

基因组不稳定性引起的基因突变是促使肿瘤发生发展的重要因素，但随着肿瘤的发展，快速增殖的肿瘤细胞进化出应对高强度复制压力的特殊方法，从而使肿瘤细胞逃避凋亡。肿瘤睾丸抗原SAGE1是一类重要的肿瘤候选驱动基因，虽然SAGE1已经开发为肿瘤免疫治疗疫苗，但是它在肿瘤发生发展中的功能及机制却不清楚。本申请对SAGE1的功能机制进行了初步探究，发现：SAGE1促进肿瘤细胞的增殖并与不良预后密切相关；参与调控复制压力和DNA双链损伤修复等通路；并与INTS3-hSSB1复合物相互作用。我们推测SAGE1通过INTS3-hSSB1调控基因组稳定性，从而增加肿瘤的化疗抵抗力。我们拟通过以下研究证实该假设：探究SAGE1对基因组稳定性的影响；SAGE1调控基因组稳定性的分子机制；探究SAGE1敲除联合PARP抑制剂对PDX小鼠的治疗效果。该研究将为肿瘤的发生发展提供新的作用机制及特异性治疗靶点。

Gene mutations caused by genomic instability are important for tumorigenesis, but as the development of tumors, rapidly proliferating tumor cells evolve special methods to cope with high replication stress, thus allowing tumor cells to escape apoptosis. Cancer-Testis Antigen SAGE1 is an important candidate tumor driver gene. Although SAGE1 has been developed as tumor immunotherapy vaccine, its function and mechanism in tumorigenesis and development are rarely studied. In this study, the functional mechanism of SAGE1 was preliminarily explored: we found that SAGE1 promote the proliferation of tumor cells and have a poor prognosis; regulate the pathways of replication fork restart and DNA double strand damage repair; and interact with INTS3-hSSB1 complex. We speculate that SAGE1 promotes chemo-resistance by regulating genomic stability through INTS3-HSSB1. We intend to confirm this hypothesis through the following studies: to study the effect of SAGE1 on genome stability; study the molecular mechanism of SAGE1 regulating genomic stability; combinate SAGE1-shRNA AAV with PARP inhibitors to treat PDX mice. This study will provide a new mechanism and specific therapeutic target for tumorigenesis.