结直肠癌(CRC)是世界第三高发恶性肿瘤，其机理尚未阐明。长链非编码RNA（lncRNA）是一类数量巨大的调控性RNA分子，与肿瘤的发生发展密切相关。申请人前期通过多角度筛选，发现一个新的功能性lncRNA—DLGAP1-AS2；它在CRC等多种肿瘤中的表达显著上调，并可促进CRC增殖和耐药，预示不良预后；初步研究提示DLGAP1-AS2可结合DDX6，增强c-Myc活性并受c-Myc反馈激活。据此，我们提出假说：DLGAP1-AS2是一个新的癌基因，通过结合DDX6，激活癌蛋白c-Myc，且其表达受到c-Myc正反馈调控，最终形成DLGAP1-AS2—DDX6/c-Myc—DLGAP1-AS2调控环路促进CRC发生发展。本项目拟在细胞、动物水平和临床样本中系统研究DLGAP1-AS2在CRC发生发展中的作用及其临床意义，并进一步阐明其机理，为解释CRC的发病机制及防治提供新的依据。

Colorectal cancer (CRC) is the third most common human malignant tumors worldwide. Long non-coding RNAs (lncRNA) are most common regulatory RNA molecules, and are closely involved in the development and progression of human tumors. By multi-dimension screening, we identified a novel functional lncRNA—DLGAP1-AS2. DLGAP1-AS2 was upregulated significantly in many types of human cancers, including CRC. Moreover, the overexpression of DLGAP1-AS2 was associated with poor prognosis and enhanced CRC growth and chemoresistance. Primary mechanistic analyses suggest that DLGAP1-AS2 could bind DDX6 and then regulate c-Myc signaling, and c-Myc is a potential transcription factor for DLGAP1-AS2. Thus, we proposed that DLGAP1-AS2 is a novel oncogene; it could activate DDX6/c-Myc pathway by binding DDX6, and was positively regulated by c-Myc. Basing on these important new findings, this project plans to further evaluate the roles, clinical significance, and molecular mechanism of DLGAP1-AS2 in the development and progression of CRC through the in vitro and in vivo as well as clinical studies. This study will provide novel ideals for explaining the pathogenesis and for the preventing and therapy of CRC.