TFE3融合蛋白在成人Xp11.2易位性肾癌中的作用及作用机制的初步研究

Adult Xp11.2 translocation renal cell carcinomas are a recently recognized distinct subtype which is characterized by various translocations at chromosome Xp11.2. The incidence of the disease has been seriously underestimated and misdiagnosed as clear cell renal cell carcinoma or papillary renal cell carcinoma because of poor understanding. Since the disease is very insensitive to immunotherapy which is commonly administrated for renal cell carcinoma, misdiagnose might seriously delay the treatment. As a transcription factor, the TFE3 fusion protein formed by Xp11.2 translocation, consistently activates its target genes, leading the malignant transformation from renal tubular cells to renal cell carcinoma. Because the adult Xp11.2 translocation renal cell carcinomas were identified recently, the function of TFE3 fusion and its target genes has not been intensively investigated. We recently established the first PRCC-TFE3 Xp11.2 translocation renal cell carcinomas cell line in the world. Based on our previous study, we aim to delineate the oncological role of TFE3 fusion during the tumorigenesis of the disease and identify its target genes and downsteam pathways. The project promises to improve our understanding of the mechanisms underlying the Xp11.2 translocation renal cell carcinoma and pave a novel approach toward target therapies.

成人Xp11.2易位性肾癌是一类近来被确定以X染色体p11.2区与其他染色体发生易位为特征的肾细胞癌亚型。由于人们对其认识不足，该病发病率被明显低估并常被误诊为肾透明细胞癌或乳头状癌。因为成人Xp11.2易位性肾癌对于肾癌常用的免疫治疗无效，误诊严重延误其治疗。Xp11.2染色体易位形成的TFE3融合蛋白作为转录因子持续激活下游肿瘤相关靶基因从而导致肾小管细胞的恶性转化。由于这类肾癌被发现较晚，目前人们对于TFE3融合蛋白的作用机制及其下游靶基因了解甚少。我们近期建成世界第一株成人PRCC-TFE3型Xp11.2易位性肾癌细胞系。本课题拟以此为基础，深入探讨TFE3融合蛋白在成人Xp11.2易位性肾癌细胞中的肿瘤生物学作用并筛查TFE3融合蛋白的靶基因及其所激活的下游通路。本研究对于深入了解TFE3融合蛋白导致成人Xp11.2易位性肾癌细胞发生的作用机制和寻找潜在靶向治疗位点具有重要意义。

成人Xp11.2易位性肾癌是一类近来被确定以X染色体p11.2区与其他染色体发生易位为特征的肾细胞癌亚型。Xp11.2染色体易位形成的TFE3融合蛋白作为转录因子持续激活下游肿瘤相关靶基因从而导致肾小管细胞的恶性转化。本课题探讨TFE3融合蛋白在成人Xp11.2易位性肾癌细胞中的肿瘤生物学作用并筛查TFE3融合蛋白的靶基因及其所激活的下游通路。在过去一年中，我们的研究基本按照《计划书》顺利执行，在工作过程中根据研究发现做出相应调整。我们的研究要点分以下部分：（1）构建肾癌Xp11.2染色体易位形成的TFE3融合蛋白的FISH探针并应用于临床病理诊断；（2）以FU-UR-1细胞系为基础探讨TFE3融合蛋白在成人Xp11.2易位性肾癌细胞中的肿瘤生物学作用并筛查TFE3融合蛋白的靶基因及其所激活的下游通路。具体执行情况为: （1）成功构建Xp11.2染色体易位形成的TFE3融合蛋白的FISH探针并顺利应用于临床病理诊断；（2）初步研究了TFE3融合蛋白在成人Xp11.2易位性肾癌细胞中的肿瘤生物学作用；（3）完成了TFE3融合蛋白的靶基因及其所激活的下游通路的全基因组芯片研究。