TFE3基因断裂和融合在Xp11.2 易位性肾癌中的致病机制研究

Xp11.2易位性肾癌是独立肾癌亚型，好发于45岁以下人群，预后差于其它类型肾癌，同时该病自身表型存在性别差异和分型差异，可能与男女X染色体的差异及TFE3基因的融合机制不同有关，但具体机制不明。我们前期发明的分离探针以及初步研究的双融合探针确定了X染色体的TFE3基因断裂及部分TFE3基因融合类型，但在占发病多数的女性病人中还未能明确TFE3基因断裂点的X染色体起源以及不同基因融合类型及其产物TFE3蛋白对性别和分型差异的作用机制。本项目将在前期工作基础上通过研发三色探针进一步确定TFE3基因断裂并明确断裂点的X染色体起源，同时在不同融合类型的Xp11.2易位性肾癌细胞系中分析融合基因启动子强度及其对TFE3蛋白表达的影响，明确TFE3基因断裂和融合产物TFE3蛋白对肾癌发病和发展的作用机制。研究结果将为寻找Xp11.2易位性肾癌治疗的分子靶点奠定理论基础。

Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 RCC) primarily affects patients younger than 45 years with poor prognosis and presents clinical variations in gender and subtypes, in which it has been speculated to be associated with the effects of X chromosome and TFE3 gene fusion processes, but much less is known about the exact molecular mechanisms. In our preliminary study, we using break-apart probe revealed TFE3 gene translocations, and with dual-fusion probe partly identified TFE3 gene fusions of Xp11.2 RCC subtypes. However, the effects of chromosome origin of Xp11.2 translocations on gender difference as well as the effects of TFE3 protein expressions produced by different TFE3 gene fusions on varied clinical characteristics of different subtypes are still uncertain. Based on our previous findings, further study will be performed to confirm the break-part of TFE3 gene and the origin of Xp11.2 translocation by developing three-color probe. At the same time, the activation of gene promoters of different subtypes as well as their effects on TFE3 protein expressions will be compared using Xp11.2 RCC cell lines. Furthermore, the molecular mechanism of TFE3 protein on the development and progression of Xp11.2 RCC will be demonstrated. This study will extend the understanding of the pathway of translocation, break-part and fusions of TFE3 gene underlying the mechanism of the Xp11.2 RCC differences in gender and subtypes and provide clues into the specific therapeutic target for Xp11.2 RCC.