TFE3融合蛋白及组蛋白甲基化酶SMYD3在成人TFE3融合基因肾癌中的作用及作用机制研究

Adult TFE3 fusion gene renal cell carcinoma is a new subtype kidney cancer recently defined by WHO. It is characterized by continuous expression of TFE3 fusion protein as a result of chromosome translocation. As a transcription factor, TFE3 fusion protein consistently activates its downstream genes. The disease is frequently misdiagnosed as clear cell renal cell carcinoma or papillary renal cell carcinoma because of the understandings. The function of TFE3 fusion protein and its target genes is still elusive. The applicant reported the regulation of androgen receptor by histone methyltransferase SMYD3 in the internaional top oncological journal JNCI in 2013. Recently, we found that histone methyltransferase SMYD3, an onco-protein, is over-expressed in adult TFE3 fusion gene renal cell carcinoma tissues and accumulated in nuclear, while the protein is undetectable in other kidney cancer subtypes or normal renal tissues, indicating its pro-tumorigenesis function in TFE3 fusion gene renal cell carcinoma. In this study, we aim to delineate the role of TFE3 fusion protein and SMYD3 in the disease and identify its target genes and downstream pathways. The project promises to improve our understanding of the mechanisms underlying TFE3 fusion gene renal cell carcinoma and pave a novel approach toward target therapies.

成人TFE3融合基因肾癌是近来被WHO新确认的肾癌的新亚型，它以染色体易位产生持续表达的TFE3融合蛋白为特征。TFE3融合蛋白作为转录因子持续激活下游靶基因。由于人们对其认识不足，该病常被误诊为肾透明细胞癌或乳头状癌。目前人们对于TFE3融合蛋白的作用机制及其下游的靶基因了解甚少。申请人于2013年在国际顶尖肿瘤学刊物JNCI报道组蛋白甲基化酶SMYD3对雄激素受体的调控作用。我们近来发现与肿瘤发生发展密切相关的SMYD3在成人TFE3融合基因肾癌中表达异常升高并聚积于细胞核内，而在其它类型肾癌或正常肾组织中无法被检出，提示该酶在此类肾癌中的重要作用。本课题拟探讨TFE3融合蛋白及SMYD3在成人TFE3融合基因肾癌细胞中的肿瘤生物学作用及作用机制。本研究对于深入了解此类肾癌的发病机制并寻找潜在的靶向治疗位点具有重要意义。

目前人们对于TFE3融合蛋白及SMYD3在泌尿系恶性肿瘤中的作用机制了解甚少，本课题旨在探讨TFE3融合蛋白及组蛋白甲基化酶SMYD3在成人TFE3融合基因肾癌细胞(Xp11.2易位性肾癌)中的肿瘤生物学作用及作用机制。课题研究期间，我们主要完成了以下工作：(1). 应用等重同位素多标签相对定量蛋白质组学技术（iTRAQ）对成人Xp11.2易位性肾细胞癌组织与癌旁组织差异性蛋白质的进行筛选与鉴定；(2). 完成了SMYD3在成人Xp11.2易位性肾细胞癌中的肿瘤生物学作用和机制研究。 (3). 初步完成Xp11.2易位性肾细胞癌异常蛋白信号通路的筛选鉴定工作，为进一步研究TFE3家族基因在泌尿系肿瘤中的调控作用及机制提供了多种线索和思路。总之我们的研究结果对TFE3融合基因肾癌临床诊治的创新具有重大意义。