肿瘤相关融合基因ASPSCR1-TFE3在肝癌中的表达及其功能研究

Hepatocarcinoma is one of the most common cancer , and also one of the most common cause of cancer-related death in the World. In previous research, we found that there are Copy Number deletions at 17q25.3 and Xp11.22 (OR> 7); larger sample and real-time PCR test validated the results, and the related genes ASPSCR1 and THE3 are over expressed in HCC tissues. And many study report that the ASPSCR1 and THE3 gene fusion, leading to the TFE3 high expression, which led to the TGF-β signaling pathway cascade, and resulting in tumorigenesis ultimately. The preliminary experimental results and literature as shown in the phenomenon of a high degree of overlap, suggesting that maybe there is ASPSCR1-TFE3 gene fusion in HCC..This project will identify the molecular mechanism of APSPCR1-TFE3 in Hepatocarcinoma as well as discuss the possibillity of ASPSCR1-TFE3 targeting in treatment of Hepatocarcinoma.

肝癌位居世界高发肿瘤的前三位，但其发病机制仍不明确。项目前期工作发现肝癌患者在17q25.3和 Xp11.22有拷贝数缺失（OR>7）；扩大样本和实时PCR重复验证结果一致。更重要的是经RT-PCR检测发现其相关基因ASPSCR1、THE3在肝癌组织中表达高于正常组织。查阅文献发现ASPSCR1与THE3发生基因融合，导致TFE3高表达，从而引起TGF-β信号通路级联放大，最终导致肿瘤的发生。初步实验结果与文献所示现象高度重合，提示肝癌中可能存在ASPSCR1-TFE3基因融合及其致病机制。.为证实以上推测，本项目将通过FISH，巢式PCR，ChIP-seq、免疫共沉淀等分子生物学、细胞生物学和体内动物实验，对ASPSCR1-TFE3融合基因及其介导的TGF信号通路促肝癌发生的分子机制进行深入研究，并最终探讨ASPSCR1-TFE3基因融合及靶向治疗肝癌的可能性。

1.研究背景：. 肝癌位居世界高发肿瘤的前三位，但其发病机制仍不明确。前期研究结果提示肝癌中可能存在ASPSCR1-TFE3基因融合。据此我们提出假设肝癌中可能存在ASPSCR1-TFE3基因融合，并对功能进行研究。.2.主要研究内容:.(1)本课题在前期研究基础上进一步通过大样本筛选，采用原位杂交技术及免疫组化在180例肝癌组织芯片中检测， 结果发现在肝癌中存在ASPSCR1-TFE3基因融合。.(2)进一步细胞实验研究转染融合基因ASPSCR1-TFE3融合基因的功能，结果发现此融合基因促进肿瘤细胞的转移性和侵袭性。.(3)进一步动物实验证实ASPSCR1-TFE3融合基因的裸鼠成瘤性阳性。.3.重要结果：.(1)证实在肝癌中存在基因融合。.(2)细胞实验及动物实验证实ASPSCR1-TFE3融合基因促进肿瘤转移性和侵袭性.科学意义:通过此课题，证实在肝癌中也存在基因融合现象，为肿瘤的分子发生机制提供了新的思路。